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A probabilistic model for predicting hypoglycemia in type 2 diabetes mellitus: The Diabetes Outcomes in Veterans Study (DOVES).

BACKGROUND: To develop and validate a method for estimating hypoglycemia risk in stable, insulin-treated subjects with type 2 diabetes mellitus. METHODS: Subjects (n = 195) monitored their blood glucose levels 4 times daily for 8 weeks. An 8-week mean blood glucose value (GLUMEAN) with standard deviation (GLUSD) was derived for each patient. Subjects were then randomly allocated to a derivation or validation set. For the derivation set, we developed a logistic function based on GLUMEAN and GLUSD to describe the 8-week risk of hypoglycemia (blood glucose < or =60 mg/dL [3.3 mmol/L]). This function was used to assign a predicted probability of hypoglycemia to each subject in the validation set. Subjects were assigned to risk quartiles and followed up for up to 52 weeks. RESULTS: We evaluated 195 subjects, 95% of whom were men and 69% of whom were non-Hispanic white. For 72 derivation subjects, GLUMEAN and GLUSD were highly influential determinants of hypoglycemia during intensified monitoring. The 123 validation subjects were followed up for 39.7 +/- 7.1 weeks (mean +/- SD). The occurrence of long-term hypoglycemia differed significantly across risk quartiles (19.4%, 36.7%, 61.3%, and 77.4%, respectively; P<.001). Receiver operating characteristic curve analysis showed that the area for the probability function (0.746 +/- 0.046) was significantly higher than the area for hemoglobin A1c (0.549 +/- 0.052) because their 95% confidence intervals did not overlap. The function also identified subjects who developed long-term hypoglycemia at a rate exceeding the median frequency. CONCLUSIONS: Self-monitoring of blood glucose is superior to hemoglobin A1c measurement in predicting long-term hypoglycemia in persons with type 2 diabetes. The risk of hypoglycemia associated with treatment intensification may be offset by strategies that reduce glucose variability.

Adult↗

A probabilistic model for genetic recombination of nonreplicating lambda-phage DNA, stimulated by "mismatch repair" of UV photoproducts.

Genetic recombination of nonreplicating phage lambda-DNA, during infection of homoimmune lysogenic bacteria, was previously observed to be dramatically stimulated by prior uv irradiation of the phages, even when the Escherichia coli hosts lacked the major uv-photo-product excision-repair system (UvrABC). UvrABC-independent recombination of circular phage molecules depends on host MutHLS functions and on undermethylation of adenines at GATC sites in the phage DNA, and thus appears to be the result of "mismatch repair" of uv photoproducts. Recombinant frequencies pass through a relatively sharp maximum at 20 J/m2 and decrease at higher doses, whereas most plausible models for the process predict monotonic increases with dose, or a plateau at high uv doses. A uv-dose-dependent loss of biological activity (restriction) of all intracellular phage DNA was also observed previously. In order to provide a framework for testing possible explanations for the unusual recombinant-frequency vs uv-dose curve, a statistical model was constructed. This model includes probability terms for all possible one-exchange and two-exchange recombination processes, and incorporates the assumption that dimer recombinants are more susceptible to restriction than monomer parents (or recombinants), because of their larger target size. By adjustment of model parameters, particularly epsilon, the efficiency per photoproduct of initiation of a recombinational exchange, a theoretical dose-response curve that agreed well with experiment was obtained. The best fit corresponded to epsilon = 0.035, close to the previously observed restriction efficiency of 0.053. In the calculations, the value for h0, the average length of heteroduplex DNA, was taken to be 0.5 lambda units, i.e., about 25 kilobase pairs. This estimate for h0 was obtained here by analysis of the density distributions of the progeny of crosses between nonreplicating density-labeled lambda-phage chromosomes, published by others [M. S. Fox, C. S. Dudney and E. J. Sodergren (1979) Cold Spring Harbor Symposium on Quantitative Biology, Vo. 43, pp. 999-1007].

Bacteriophage lambda↗

A probabilistic model for deriving soil quality criteria based on secondary poisoning of top predators. I. Model description and uncertainty analysis.

In previous studies, the risk of toxicant accumulation in food chains was used to calculate quality criteria for surface water and soil. A simple algorithm was used to calculate maximum permissable concentrations [MPC = no-observed-effect concentration/bioconcentration factor(NOEC/BCF)]. These studies were limited to simple food chains. This study presents a method to calculate MPCs for more complex food webs of predators. The previous method is expanded. First, toxicity data (NOECs) for several compounds were corrected for differences between laboratory animals and animals in the wild. Second, for each compound, it was assumed these NOECs were a sample of a log-logistic distribution of mammalian and avian NOECs. Third, bioaccumulation factors (BAFs) for major food items of predators were collected and were assumed to derive from different log-logistic distributions of BAFs. Fourth, MPCs for each compound were calculated using Monte Carlo sampling from NOEC and BAF distributions. An uncertainty analysis for cadmium was performed to identify the most uncertain parameters of the model. Model analysis indicated that most of the prediction uncertainty of the model can be ascribed to uncertainty of species sensitivity as expressed by NOECs. A very small proportion of model uncertainty is contributed by BAFs from food webs. Correction factors for the conversion of NOECs from laboratory conditions to the field have some influence on the final value of MPC5, but the total prediction uncertainty of the MPC is quite large. It is concluded that the uncertainty in species sensitivity is quite large. To avoid unethical toxicity testing with mammalian or avian predators, it cannot be avoided to use this uncertainty in the method proposed to calculate MPC distributions. The fifth percentile of the MPC is suggested as a safe value for top predators.

Algorithms↗

A probabilistic model for deriving soil quality criteria based on secondary poisoning of top predators. II. Calculations for dichlorodiphenyltrichloroethane (DDT) and cadmium.

A simplified food web with three trophic levels is designed: plants and invertebrates at the first, small birds and mammals at the second, and birds and beasts of prey at the third trophic level. Exposure of top predators via separate food chains is analyzed. However, most top predator species are exposed via more than one food chain (food web). Therefore, a species-specific approach is followed too, for which four bird of prey species and two beast of prey species with different food choices are selected: sparrow hawk, kestrel, barn owl, little owl, badger, and weasel. The most critical food chains for secondary poisoning of top predators are soil --> worm/insect --> bird --> bird of prey for dichlorodiphenyltrichloroethane (DDT), and soil --> worm --> bird/mammal --> bird of prey for cadmium (Cd). The risk for the selected top predator species is much lower than the risk based on these critical food chains because the critical food chains constitute a minor part of their food webs. Species feeding on birds (sparrow hawk) and small carnivorous mammals (barn owl) are exposed to DDT and Cd to a much higher extent than species mainly feeding on small herbivorous mammals (kestrel and weasel). It is recommended to include exposure via the pathways soil --> worm/insect --> bird/mammal --> top predator in procedures for derivation of environmental quality objectives for persistent and highly lipophilic compounds.

Animal Feed↗

Gene amplification by unequal sister chromatid exchange: probabilistic modeling and analysis of drug resistance data.

Unequal sister chromatid exchange has been proposed as one of several possible mechanisms for gene amplification resulting in tandemly repeated sequences on chromosomes. Two requirements for testing this hypothesis are analytical observations and a mathematical model. Recently observations were reported for the number of tandemly repeated sequences on chromosomes of cells growing in the presence of a toxic drug and the mechanism was proposed to be unequal sister chromatid exchange. We now develop a mathematical model of this process based on the following hypotheses, (i) the extent of slippage between paired sister chromatids is a random variable with geometric distribution, (ii) the number of crossover sites is a random variable with a Poisson distribution, and (iii) cells with less than a threshold number of copies of an essential gene are eliminated when grown in selective conditions. Iterating the model at successive cell divisions results in a Markov chain with a denumerable infinity of states. The resulting distributions of gene copy number per cell at a particular population size are compared to published data on the CAD gene in BHK cells growing in the presence of the drug PALA (Smith et al., 1990, Cell, 63, 1219). The mathematical model can reproduce the observed means and standard deviations of gene copy number per cell and allows construction of confidence region estimates of parameters describing the extent of slippage, density of crossover sites, and strength of selection. An important prediction of the model is that in non-selective conditions the cells with amplified sequences gradually disappear from the population even if they are not at a growth disadvantage, though rare cells with a very large number of amplified sequences might continue to exist. The success of modeling suggests that the proposed mechanism of gene amplification by unequal sister chromatid exchange is consistent with the number of tandemly repeated sequences on chromosomes observed in some circumstances.

Animals↗

A probabilistic model for ligand-cytoskeleton transmembrane adhesion: predicting the behavior of microspheres on the surface of migrating cells.

A theoretical model describing the attachment and cytoskeletal coupling of microspheres to the dorsal surface of motile cells was developed. Integral membrane receptors beneath a ligand-coated microsphere are allowed to be either free, attached to the microsphere, bound to the rearward moving actin network, or linked to both the bead and the cytoskeleton, and to switch between these four states. The binding transitions being modeled as chemical reactions governed by rate constants taken from literature, the chance for a receptor to be in each binding state over time is obtained by solving mass-balance equations for the probability functions. The population of n such receptors beneath the microsphere is accounted for by a binomial distribution for each state. Adhesion and transmembrane coupling (resulting in microsphere transport) being defined by a minimal number of ligand-receptor and receptor-cytoskeleton bonds, respectively, the probabilities of attachment and transport of the microsphere over time are expressed in terms of state probability distributions. It is found that increasing the ligand density raises the attachment and transport probabilities, in good quantitative agreement with recent experiments using optical tweezers and accurate position tracking. Increasing the bead size does not affect attachment, but raises the transport probability with a marked transition for bead diameter around 100 nm, as for experimental data. Increasing the restraining force decreases the transport probability, probably by inducing a rupture of receptor-cytoskeleton bonds. This study thus provides a framework that helps understand the process of cortical flow associated with cell locomotion.

Animals↗

Automatic cerebrovascular segmentation by accurate probabilistic modeling of TOF-MRA images.

Accurate automatic extraction of a 3D cerebrovascular system from images obtained by time-of-flight (TOF) or phase contrast (PC) magnetic resonance angiography (MRA) is a challenging segmentation problem due to small size objects of interest (blood vessels) in each 2D MRA slice and complex surrounding anatomical structures, e.g. fat, bones, or grey and white brain matter. We show that due to a multi-modal nature of MRA data blood vessels can be accurately separated from background in each slice by a voxel-wise classification based on precisely identified probability models of voxel intensities. To identify the models, an empirical marginal probability distribution of intensities is closely approximated with a linear combination of discrete Gaussians (LCDG) with alternate signs, and we modify the conventional Expectation-Maximization (EM) algorithm to deal with the LCDG. To validate the accuracy of our algorithm, a special 3D geometrical phantom motivated by statistical analysis of the MRA-TOF data is designed. Experiments with both the phantom and 50 real data sets confirm high accuracy of the proposed approach.

Algorithms↗

Probabilistic models of genome shuffling.

The comparison of entire genomes in evolutionary studies gives rise to alignments characterized by many intersections, or inversions in the order of two fragments in different genomes. To model this, we suggest a random migration process for fragments, and discuss its equilibrium distribution in the case of linear and circular genomes. Simulations are carried out to explore "cut-off" behavior as the process approaches equilibrium. We define a new process to take into account the indistinguishability of two fragments which are adjacent in both genomes being compared. Questions of applicability of these models are discussed.

Biological Evolution↗

A probabilistic model of glenohumeral external rotation strength for healthy normals and rotator cuff tear cases.

The reigning paradigm of musculoskeletal modeling is to construct deterministic models from parameters of an "average" subject and make predictions for muscle forces and joint torques with this model. This approach is limited because it does not perform well for outliers, and it does not model the effects of population parameter variability. The purpose of this study was to simulate variability in musculoskeletal parameters on glenohumeral external rotation strength in healthy normals, and in rotator cuff tear case using a Monte Carlo model. The goal was to determine if variability in musculoskeletal parameters could quantifiably explain variability in glenohumeral external rotation strength. Multivariate Gamma distributions for musculoskeletal architecture and moment arm were constructed from empirical data. Gamma distributions of measured joint strength were constructed. Parameters were sampled from the distributions and input to the model to predict muscle forces and joint torques. The model predicted measured joint torques for healthy normals, subjects with supraspinatus tears, and subjects with infraspinatus-supraspinatus tears with small error. Muscle forces for the three conditions were predicted and compared. Variability in measured torques can be explained by differences in parameter variability.

Computer Simulation↗

A probabilistic model of bathing beach safety.

An improved mathematical model for bathing beach safety is proposed. It is derived by joining the probability of infection from a given dose (Poisson distribution and the probability of acquiring such a dose (lognormal distribution). Even in the absence of better clinical and epidemiological data, the model permits an assessment of relative risk from certain hazards and the design of more meaningful bacteriological standards for individual beaches.

Bacteria↗

Assessing aggregate and cumulative pesticide risks using a probabilistic model.

Determining aggregate and cumulative risks from exposures to pesticides presents a number of challenges. The analysis must capture the correlations in residues that occur from both additive and exclusionary processes in the use of pesticides. The analysis also requires a quantitative mechanism for evaluating risks associated with exposures to mixtures of pesticides. This paper presents an analysis of aggregate exposures and risks associated with exposures to a pesticide, Alpha, and the cumulative exposure to and risk from three pesticides, Alpha, Beta, and Gamma. The cumulative risks are evaluated by determining the systemic (absorbed) doses that result from inhalation, dermal, and oral exposures to the pesticides. A 'relative toxicity' model is used to evaluate cumulative risks. The assessment of cumulative exposure was performed using the LifeLine Version 1.0. The model simulates pesticide exposure using an individual-based approach where daily exposures are evaluated for each person, season, and location.

Administration, Cutaneous↗