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PubMed2005

The formulation of the control of an expression pattern in a gene network by propositional calculus.

In this study we model a gene network as a continuous-time switching network. In this model, each gene has a binary state which indicates if the gene expresses or not. We propose a method to control a sequence of expression patterns in the gene network model by adding another continuous-time switching network. By using propositional calculus, we will show that the control problem can be formulated as a mixed-integer linear programming problem with linear constraints.

Animals↗

PubMed2004

Enriching the sequence substitution matrix by structural information.

A fundamental step in homology modeling is the comparison of two protein sequences: a probe sequence with an unknown structure and function and a template sequence for which the structure and function are known. The detection of protein similarities relies on a substitution matrix that scores the proximity of the aligned amino acids. Sequence-to-sequence alignments use symmetric substitution matrices, whereas the threading protocols use asymmetric matrices, testing the fitness of the probe sequence into the structure of the template protein. We propose a linear combination of threading and sequence-alignment scoring function, to produce a single (mixed) scoring table. By fitting a single parameter (which is the relative contribution of the BLOSUM 50 matrix and the threading energy table of THOM2) we obtain a significant increase in prediction capacity in the twilight zone of homology modeling (detecting sequences with <25% sequence identity and with very similar structures). For a difficult test of 176 homologous pairs, with no signal of sequence similarity, the mixed model makes it possible to detect between 40 and 100% more protein pairs than the number of pairs that are detected by pure threading. Surprisingly, the linear combination of the two models is performing better than threading and than sequence alignment when the percentage of sequence identity is low. We finally suggest that further enrichment of substitution matrices, combing more structural descriptors such as exposed surface area, or secondary structure is expected to enhance the signal as well.

Algorithms↗

PubMed1992

Heterogeneous sexual mixing in populations with arbitrarily connected multiple groups.

"A simple procedure for constructing [social/sexual] mixing models for arbitrarily classified (e.g. by sex, age, geographical location, sexual preference) populations is outlined, including a scheme for finding the number of independent mixing parameters required, and a simple (linear algebra) means for finding the values of the dependent mixing parameters. Various worked examples are presented, including the two-sex problem and structured and selective mixing." The use of the models for analyzing mixing structures for AIDS transmission is assessed. (SUMMARY IN FRE)

Acquired Immunodeficiency Syndrome↗

PubMed2006

Semi-empirical power-law scaling of new infection rate to model epidemic dynamics with inhomogeneous mixing.

The expected number of new infections per day per infectious person during an epidemic has been found to exhibit power-law scaling with respect to the susceptible fraction of the population. This is in contrast to the linear scaling assumed in traditional epidemiologic modeling. Based on simulated epidemic dynamics in synthetic populations representing Los Angeles, Chicago, and Portland, we find city-dependent scaling exponents in the range of 1.7-2.06. This scaling arises from variations in the strength, duration, and number of contacts per person. Implementation of power-law scaling of the new infection rate is quite simple for SIR, SEIR, and histogram-based epidemic models. Treatment of the effects of the social contact structure through this power-law formulation leads to significantly lower predictions of final epidemic size than the traditional linear formulation.

Chicago↗

PubMed1995

[Evaluation of partial volume effect in quantitative measurement of regional cerebral blood flow using positron emission tomography].

Effects of limited spatial resolution of the positron emission tomography (PET) scanner on the quantitative measurement of regional cerebral blood flow (rCBF) was investigated for various tracer kinetic models with use of 15O labeled water and PET. Using a numerical brain phantom consisting of a gray matter, white matter and cerebrospinal fluid components, dynamical tracer distribution images were calculated for the H215O bolus injection and for the C15O2 gas inhalation protocols. The tracer distribution images were convoluted with a 2 dimensional gaussian function with full-width at half maximum (FWHM) of 4, 7, 12 mm to simulate a limited spatial resolution of the PET scanner, and rCBF images were calculated according to some kinetic models. Smoothing the tracer distribution images caused a heterogeneous structure (tissue mixture) in a given volume element. rCBF values calculated by models with use of 15O-water and PET were found to provide rCBF values that were systematically underestimated compared with those obtained by the microsphere model for a mixed tissue region. Moreover, the magnitude of the underestimation was shown to be highly dependent on the tracer kinetic models employed, those errors for mixed tissue of gray and white matter were 20% on steady state, 9% on autoradiography and on weighted integration method, and 2% on non-linear least squares fitting, compared with microsphere model. More errors observed by steady state method and autoradiography method happened for tissue mixture consisting gray matter, white matter and cerebrospinal fluid components. It is important to take into account for difference of the partial volume effect for each models in calculated rCBF.

Brain↗

PubMed2000

Commentary: using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics.

The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyama in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application.

Algorithms↗

PubMed2006

Identification and quantification of protein carbonylation using light and heavy isotope labeled Girard's P reagent.

Protein carbonyls are one of the most widely studied markers of oxidative stress. Determining increases in the concentration of protein carbonyls known to be associated with neurodegenerative diseases, heart disease, cancer and ageing. Identification of carbonylation sites in oxidized proteins has been a challenge. Even though recent advances in proteomics has facilitate the identification of carbonylation sites in oxidized proteins, confident identification remains a challenge due to the complicated nature of oxidative damage and the wide range of oxidative modifications. Here, we report the development of a multiplexing strategy that facilitates confident carbonylated peptide identification through a combination of heavy and light isotope coding and a multi-step filtering process. This procedure involves (1) labeling aliquots of oxidized proteins with heavy and light forms of Girard's reagent P (GPR) and combining them in a 1:1 ratio along with (2) LC/MS and MALDI-MS/MS analysis. The filtering process uses LC/MS and MALDI-MS/MS data to rule out false positives by rejecting peptide doublets that do not appear with the correct concentration ratio, retention time, tag number, or resolution. This strategy was used for the identification of heavily oxidized transferrin peptides and resulted in identification 13 distinct peptides. The competency of the method was validated in a complex mixture using oxidized transferrin in a yeast lysate as well as oxidized yeast. Twenty-five percent of the peptides identified in a pure oxidized sample of transferrin were successfully identified from the complex mixture. Analysis of yeast proteome stressed with hydrogen peroxide using this multiplexing strategy resulted in identification of 41 carbonylated peptides from 36 distinct proteins. Differential isotope coding of model peptides at different concentrations followed by mixing at different ratios was used to establish the linear dynamic range for quantification of carbonylated peptides using light and heavy forms of GPR.

Amino Acid Sequence↗

PubMedDate not supplied

The effect of using approximate gametic variance covariance matrices on marker assisted selection by BLUP.

Under additive inheritance, the Henderson mixed model equations (HMME) provide an efficient approach to obtaining genetic evaluations by marker assisted best linear unbiased prediction (MABLUP) given pedigree relationships, trait and marker data. For large pedigrees with many missing markers, however, it is not feasible to calculate the exact gametic variance covariance matrix required to construct HMME. The objective of this study was to investigate the consequences of using approximate gametic variance covariance matrices on response to selection by MABLUP. Two methods were used to generate approximate variance covariance matrices. The first method (Method A) completely discards the marker information for individuals with an unknown linkage phase between two flanking markers. The second method (Method B) makes use of the marker information at only the most polymorphic marker locus for individuals with an unknown linkage phase. Data sets were simulated with and without missing marker data for flanking markers with 2, 4, 6, 8 or 12 alleles. Several missing marker data patterns were considered. The genetic variability explained by marked quantitative trait loci (MQTL) was modeled with one or two MQTL of equal effect. Response to selection by MABLUP using Method A or Method B were compared with that obtained by MABLUP using the exact genetic variance covariance matrix, which was estimated using 15,000 samples from the conditional distribution of genotypic values given the observed marker data. For the simulated conditions, the superiority of MABLUP over BLUP based only on pedigree relationships and trait data varied between 0.1% and 13.5% for Method A, between 1.7% and 23.8% for Method B, and between 7.6% and 28.9% for the exact method. The relative performance of the methods under investigation was not affected by the number of MQTL in the model.

Chromosome Mapping↗

PubMed1993

Estimating treatment means in a mixed-effect ANOVA model for bioequivalence studies.

In order to establish bioequivalence between two formulations in a crossover trial, it is common to assume a mixed-effect analysis of variance (ANOVA) model and perform two one-sided tests. When the analysis is done on the untransformed data, the numerators of the test statistics are not, in general, treatment contrasts. Consequently, the standard errors of the numerators are difficult to compute. The usual practice is to approximate these with the standard errors of treatment contrasts (the "usual approximation"). This paper examines the goodness of this approximation. We present a few technical issues involved in analyzing the untransformed data with a mixed-effect ANOVA model, and state a parametric definition for the terminology "treatment means." The best linear unbiased estimator (BLUE) for the treatment means is derived, as well as its covariance matrix. Due to the presence of the intersubject variability, the variances and covariances of the BLUE of the treatment means are much larger than is commonly believed. A simulation study shows that these larger-than-expected variances/covariances may widen the usual approximate 90% confidence interval by as much as 10%.

Analysis of Variance↗

PubMed2002

Comparison of end-tidal CO2 and Paco2 in children receiving mechanical ventilation.

OBJECTIVE: To determine whether end-tidal CO(2) (Petco(2)) measurement provides a reliable estimate of ventilation in critically ill children who are mechanically ventilated. DESIGN: Prospective, nonrandomized, consecutive enrollment study. SETTING: A university-affiliated children's hospital pediatric intensive care unit. PATIENTS: All intubated, mechanically ventilated pediatric patients. INTERVENTIONS: All Petco(2)-Paco(2) pairs were from patients ventilated with a Servo 300 Ventilator (Siemens-Elema AB, Stockholm, Sweden). When a blood gas sample was obtained, Petco(2) as measured by a continuous mainstream Petco(2) capnograph was recorded. Measurements: The results of blood gas measurements and corresponding Petco(2) measurements were recorded. Demographic data and primary diagnosis were noted. Petco(2)-Paco(2) pairs obtained from patients with intracardiac shunts or obtained during high-frequency oscillation or extracorporeal membrane oxygenation at the time of measurement were excluded from analysis. Linear regression was used to analyze Petco(2)-Paco(2) pairs. Repeated measure analysis of variance with the mixed-model algorithm in SAS software (SAS Institute, Carey, NC) was used to analyze the trend in the Petco(2) and Paco(2) relationship. Chi-square was used to analyze categorical data. Statistical significance was considered p <.05. RESULTS: A total of 129 children were enrolled, and 1708 paired Paco(2) and Petco(2) measurements were recorded. The mean age +/- sd was 4.1 +/- 5.6 yrs. Paco(2) positively correlated with Petco(2). The linear equation for the regression analysis was y = 0.71x (95% confidence interval, 0.69-0.73) + 8.93 (95% confidence interval, 7.89-9.97), with r (2) =.716 and p <.001. The Petco(2)-Paco(2) difference was </=5 mm Hg (0.67 kPa) in 54% and </=10 mm Hg (1.33 kPa) in 80% of paired data. Increased lung disease had a negative effect on Petco(2) correlation with Paco(2). A total of 223 of 640 (35%) blood gases (defined by Pao(2)/Fio(2) ratio of <200) had >10 mm Hg (1.33 kPa) difference between the Petco(2) and Paco(2). However, only 111 of 1068 (10%) Petco(2)-Paco(2) pairs had a difference of >10 mm Hg (1.33 kPa) in patients with a Pao(2)/Fio(2) ratio >200. Trend analysis showed the Petco(2)-Paco(2) difference increased with increasing duration of mechanical ventilation. CONCLUSION: In most intubated, mechanically ventilated infants and children, Petco(2) reliably estimates ventilation.

Journal Article↗

PubMed1989

A non-linear multi-criteria programming approach for determining county emergency medical service ambulance allocations.

In this paper an integer, non-linear mathematical programming model is developed to allocate emergency medical service (EMS) ambulances to sectors within a county in order to meet a government-mandated response-time criterion. However, in addition to the response-time criterion, the model also reflects criteria for budget and work-load, and, since ambulance response is best described within the context of a queueing system, several of the model system constraints are based on queueing formulations adapted to a mathematical programming format. The model is developed and demonstrated within the context of an example of a county encompassing rural, urban and mixed sectors which exhibit different demand and geographic characteristics. The example model is solved using an integer, non-linear goal-programming technique. The solution results provide ambulance allocations to sectors within the county, the probability of an ambulance exceeding a prespecified response time, and the utilization factor for ambulances per sector.

Ambulances↗

PubMed1991

Nonlinear dobutamine pharmacokinetics in a pediatric population.

OBJECTIVE: To evaluate a linear kinetic model for dobutamine clearance. DESIGN: A prospective evaluation of pediatric patients receiving continuous infusions of dobutamine at varying doses. SETTING: A pediatric critical care unit. PATIENTS: Twelve patients age 2 days to 9 yrs and weighing 2.7 to 33 kg who required vasopressor therapy. Infusion rates for dobutamine ranged from 2 to 15 micrograms/kg.min. MEASUREMENTS AND MAIN RESULTS: Serum concentrations varied from 6.4 to 347 ng/mL (21 to 1151 nmol/L). Concentration was found to increase with dose. However, the relationship of clearance to steady-state concentration had a negative slope. Values for clearance varied from 32 to 625 mL/kg.min. Multiple analysis of variance on age, weight, and co-infused dopamine showed that these factors did not influence the relationship of clearance to steady-state concentration. Analysis to show an underlying model failed to differentiate Michaelis-Menten from nonlinear binding or mixed models on the basis of these data. CONCLUSIONS: Dobutamine pharmacokinetics do not appear to follow a simple linear model. Based on the current data, neither age nor the added infusion of dopamine affects the clearance of dobutamine.

Age Factors↗

PubMed2003

[Quantification of the probability of milk contamination by Listeria monocytogenes during manufacture of hard cheese].

BACKGROUND: The present work is concerned with the probability of contamination by Listeria monocytogenes in the artisanal manufacture of Swiss Emmental hard cheese made from raw milk. The simulation model follows the evolution of the contaminant flora from raw milk at the farm to milk mixing, storage at the cheese factory and to the cheese manufacturing process. METHODS: The simulations are based on models of predictive microbiology, namely the exponential growth model of bacteria including the lag-time, a cardinal growth model and a Log-linear model of thermal deactivation of bacteria. RESULTS: The results of the actual simulation indicate that the contamination of milk at the farm is a rare event (P=0.0036), but the mixing of milk at the cheese factory leads to a higher probability of contamination of cheese milk (P=0.07). Elevated bacterial concentrations are mainly due to cases of mastitis involving Listeria monocytogenes. The decline in bacterial counts during cheese manufacture depends on the curing temperature (52-54 degrees C) and varies between 1.5 and 3.2 Log cfu/ml. Freshly manufactured Emmental-cheese made from contaminated raw milk is expected to have only 4.6 cfu of heat injured Listeria monocytogenes /kg cheese mass in the press. CONCLUSION: Depending on listeria evolution, from the press to the product consumption, consumer exposure has been evaluated and might result in 1 to 10 Listeria monocytogenes per portion of cheese. The bacterial presence could be due to recontamination during packaging, distribution and cheese preparation by the consumer. Based on the presented data and estimations, it is concluded that the consumption of traditionally/artisanal manufactured Swiss Emmental hard cheese presents an extremely low, but existent risk, especially for people with a deficient or diminished immune system.

Animals↗

PubMed2003

Hazard regression for interval-censored data with penalized spline.

This article introduces a new approach for estimating the hazard function for possibly interval- and right-censored survival data. We weakly parameterize the log-hazard function with a piecewise-linear spline and provide a smoothed estimate of the hazard function by maximizing the penalized likelihood through a mixed model-based approach. We also provide a method to estimate the amount of smoothing from the data. We illustrate our approach with two well-known interval-censored data sets. Extensive numerical studies are conducted to evaluate the efficacy of the new procedure.

Biometry↗

PubMed1987

The bootstrapped model--Lessons for the acceptance of intellectual technology.

This paper is intended as a non-technical introduction to a growing aspect of what has been termed 'intellectual technology'. The particular area chosen is the use of simple linear additive models for judgement and decision making purposes. Such models are said to either outperform, or perform at least as well as, the human judges on which they are based, hence they are said to 'bootstrap' such human inputs. Although the paper will provide a fairly comprehensive list of recent applications of such models, from postgraduate selection to judgements of marital happiness, the work will concentrate on the topic of Credit Scoring as an exemplar - that is, the assignment of credit by means of a simple additive rule. The paper will also present a simple system, due to Dawes, of classifying such models according to the form and source of their weights. The paper further discusses the reasons for bootstrapping and that other major phenomenon of such models - that is, the one can rarely distinguish between the prescriptions of such models, however the weights have been arrived at. It is argued that this 'principle of the flat maximum' allows us to develop a technology of judgement. The paper continues with a brief historical survey of the reactions of human experts to such models and their superiority, and suggestions for a better mix of expert and model on human engineering lines. Finally, after a brief comparison between expert systems and linear additive models, the paper concludes with a brief survey of possible future developments. A short Appendix describes two applications of such models.

Journal Article↗

PubMed2006

An evaluation of longitudinal neurocognitive performance among middle-aged and older schizophrenia patients: use of mixed-model analyses.

The purpose of this study was to evaluate the trajectory of neuropsychological performance among middle-aged and older patients with schizophrenia using hierarchical linear modeling (HLM). Using the Mattis Dementia Rating Scale (DRS), we assessed cognitive performance of 143 schizophrenia outpatients (Mean age=53.1 years, SD=8.8) and 66 healthy comparison subjects (Mean age=61.8 years, SD=8.8). All participants had DRS data from two or more testing sessions with average intervals between sessions being 15 months (range=6-55). Using HLM, we found cognitive performance to be stable over time in both schizophrenia patients and healthy comparison subjects. Age, gender, ethnicity, and education did not affect trajectories. We also analyzed the data using more traditional statistical approaches to longitudinal data and found similar results. In sum, we found cognitive impairment to be stable over time among outpatients with schizophrenia, regardless of the statistical methodology used to analyze longitudinal data.

Adult↗

PubMed1996

Quad-band excitation for low bit rate speech coding.

The excitation parameters of a multiband excitation model for speech production consist of a pitch period and a series of voiced/unvoiced (v/uv) decisions for a number of fixed frequency bands around the harmonics of the fundamental. In this paper, it is shown that, at most, four v/uv variable-length nonoverlapping frequency bands spanning over the telephone bandwidth are adequate to represent the excitation spectrum that provides an improved modeling of mixed voicing and noisy speech. A quad-band excitation (QBE) method is presented which generates excitation source for a linear prediction vocoder for low bit rate transmission of speech signal and the DRT scores validate the potential of the method.

Humans↗

PubMed1995

Linearity of pharmacokinetics and model estimation of sufentanil.

BACKGROUND: The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed. METHODS: The pharmacokinetics of sufentanil were investigated in 23 patients, aged 14-68 yr, scheduled for surgery with postoperative ventilation. After induction of anesthesia, sufentanil was administered as a short infusion (10-20 min) in doses ranging from 250 micrograms to 1,500 micrograms. Frequent arterial blood samples were gathered during and at the end of infusion, then at specific intervals up to 48 h after infusion. Plasma concentrations of sufentanil were measured by radioimmunoassay (limit of sensitivity 0.02 ng.ml-1). The data were analyzed with the standard two-stage, naive pooled-data and the mixed effect pharmacokinetic approaches. RESULTS: The pharmacokinetics of sufentanil were adequately described by a linear three-compartmental mamillary model with the following parameters, expressed as log mean values with 95% confidence intervals: the central volume of distribution = 14.3 l (13.1-15.41), the rapidly equilibrating volume = 63.1 l (61.9-64.3 l), the slowly equilibrating volume = 261.6 l (260.2-262.9 l), the steady-state distribution volume = 339 l (335-343 l), metabolic clearance = 0.92 l.min-1 (0.84-1.05 l.min-1), rapid distribution clearance = 1.55 l.min-1 (1.34-2.14 l.min-1), slow distribution clearance = 0.33 l.min-1 (0.27-0.49 l.min-1), and elimination half-life = 769 min (690-1011 min). No relation to age, weight, or lean body mass was found for any of the parameters. CONCLUSIONS: Sufentanil pharmacokinetics were linear within the dose range studied. Drug detection up to 24 h after dosing was necessary to define the terminal elimination phase. The metabolic clearance approached liver blood flow and a large volume of distribution was identified, consistent with the long terminal elimination half-life. Simulations predicted that plasma sufentanil steady-state concentrations would rapidly decline after termination of an infusion despite the long half-lives.

Adolescent↗