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The consequences of uncertainty for the prediction of the effects of schistosomiasis control programmes.

Progress in the development of schistosomiasis models for use in control programmes is limited by the considerable uncertainty in many of the biological parameters. In this paper, this problem is addressed by a comprehensive sensitivity analysis of a schistosomiasis model using the Latin Hypercube method. Fifty simulations with different parameter contributions are run for 50 years with treatment during the first 20 years and reinfection thereafter. The analysis shows only a relatively small divergence between simulations during the chemotherapy treatment programme but considerable divergence in reinfection levels after treatment is stopped. A skewed distribution of outcomes was seen with most simulations showing effective control and a few where control had less impact. The most important uncertainty source was due to the unknown levels of acquired immunity and also uncertainty in the true worm burden. In particular, the strength of the immune response was most important in determining whether control was effective with higher immunity leading to less effective control. Among those simulations in which control was not very effective, those in which the mean worm burden was high showed the least effective control. Since both these are areas of genuine uncertainty, it is proposed that uncertainty analysis should be an integral part of any projection of control programmes.

Humans↗

Characterizing photosynthesis and transpiration of plant communities in controlled environments.

CO2 and water vapor fluxes of hydroponically grown wheat and soybean canopies were measured continuously in several environments with an open gas exchange system. Canopy CO2 fluxes reflect the photosynthetic efficiency of a plant community, and provide a record of plant growth and health. There were significant diurnal fluctuations in root and shoot CO2 fluxes, and in shoot water vapor fluxes. Canopy stomatal conductance (Gc) to water vapor was calculated from simultaneous measurements of canopy temperature (Tcan) and transpiration rates (Tr). Tr in the dark was substantial, and there were large diurnal fluctuations in both Gc and Tr. Canopy net Photosynthesis (Pnet), Tr, and Gc increased with increasing net radiation. Gc increased with Tr, suggesting that the stomata of plants in controlled environments (CEs) behave differently from field-grown plants. A transpiration model based on measurements of Gc was developed for CEs. The model accurately predicted Tr from a soybean canopy.

Carbon Dioxide↗

Digital and sampled-data control of arterial blood pressure during halothane anesthesia.

A control system that maintains mean arterial pressure (MAP) at a desired level by automatically controlling halothane input has been developed. The control system is a discrete, digital type and is implemented with a small desk-top programmable calculator. Essentially, if MAP decreases, the inspired concentration of halothane will decrease; if MAP increases, the system will compensate by increasing inspired halothane concentration. The control system was tested in two ways: with a hybrid computer model of uptake and distribution of halothane and with dog experiments. The results indicate that (a) the model can be used to predict the response of the animal-anesthesia machine control system, and (b) the proposed algorithm is successful in controlling one anesthetic agent with one physiologic variable.

Anesthesiology↗

In vivo quantification of a homogeneous brain deformation model for updating preoperative images during surgery.

Clinicians using image-guidance for neurosurgical procedures have recently recognized that intraoperative deformation from surgical loading can compromise the accuracy of patient registration in the operating room. While whole brain intraoperative imaging is conceptually appealing it presents significant practical limitations. Alternatively, a promising approach may be to combine incomplete intraoperatively acquired data with a computational model of brain deformation to update high resolution preoperative images during surgery. The success of such an approach is critically dependent on identifying a valid model of brain deformation physics. Towards this end, we evaluate a three-dimensional finite element consolidation theory model for predicting brain deformation in vivo through a series of controlled repeat-experiments. This database is used to construct an interstitial pressure boundary condition calibration curve which is prospectively tested in a fourth validation experiment. The computational model is found to recover 75%-85% of brain motion occurring under loads comparable to clinical conditions. Additionally, the updating of preoperative images using the model calculations is presented and demonstrates that model-updated image-guided neurosurgery may be a viable option for addressing registration errors related to intraoperative tissue motion.

Animals↗

Can malaria be controlled where basic health services are not used?

OBJECTIVE: To assess the potential of integrating malaria control interventions in underused health services. METHODS: Using the Piot predictive model, we estimated malaria cure rates by deriving parameters influencing treatment at home and in health facilities from the best-performing African malaria programmes and applying them to Yanfolila district, Mali. RESULTS: Without any malaria control intervention, the population cure rate is 8.4% with home treatment, but would be 13% if access to timely treatment were improved (as in Kenya). A further 3.2% of malaria patients could be cured in institutional settings with more sensitive diagnosis, timely start of treatment, better compliance (as in Uganda, Tanzania, Ghana) and 80% chloroquine efficacy. Applied in a setting where 7.6% of malaria patients seek institutional care, these assumptions would result in a total population cure rate of 14.5%. Increasing the health service user rate from 0.17 in Yanfolila to 0.95 new cases/inhabitant/year (as in Namibia) would result in half of all malaria patients attending professional services, raising the cure rate to 26.1%. CONCLUSION: If malaria patients are to be treated and followed-up early and appropriately, basic health services need to deliver integrated care and be attended by an adequate pool of users. Improved service user rates and case management can increase malaria cure rates far more than isolated control interventions can. This has implications for international policies endorsing a narrow disease-based approach.

Africa↗

The relationship between safety climate and injury rates across industries: the need to adjust for injury hazards.

Previous studies have suggested that strong safety climates (shared perceptions of safe conducts at work) are associated with lower workplace-injury rates, but they rarely control for differences in industry hazards. Based on 33 companies, we assessed its association with injury rates using three rate based injury measures (claims per 100 employees, claims per 100,000 h worked, and claims per 1 million US dollars payroll), which were derived from workers' compensation injury claims. Linear regression models were used to test the predictability of safety climate on injury rates, followed by controlling for differences in hazard across industries gauged by national industry-specific injury rates. In the unadjusted model, company level safety climate were negatively and significantly associated with injury rates. However, all of the above associations were no longer apparent when controlling for the hazardousness of the specific industry. These findings may be due to over adjustment of hazard risk, or the overwhelming effects of industry specific hazards relative to safety climate effects that could not be differentiated with the statistical power in our study. Industry differences in hazard, conceptualized as one type of injury risk, however need to be considered when testing the association between safety climate and injury across different industries.

Accidents, Occupational↗

Some implications of the Linear Quadratic model for tumor control probability.

To define an optimal radiation therapy strategy, the dependence of the probability of cure and of significant complications, on the parameters controlled by the radiotherapist must be determined. The recent success of the Linear Quadratic (LQ) model in constructing isoeffect relations for normal tissue damage and in describing in vitro cell survival curves, indicate that this model could be used to determine this dependence. The problem of tumor control is addressed. Using LQ model parameters obtained from human tumor cell lines, the sigmoid dose-response curves for controlling tumors of fixed size but of several histologies, with a fractionated course of radiotherapy is obtained. Except for squamous cell carcinoma, the calculated average tumor control doses (TCD37 or TCD50) are unrealistically low, but the model can be made more realistic by including inhomogeneities in the spatial dose distribution and heterogeneous tumor cell populations. The slope of the dose response curves are determined and the significance of the "relative slope" parameter rho as a measure of the number of cells in a tumor's most radioresistant clone is noted. The relation of the model's predictions to qualitative features of the experimental animal data for both tumor control and for normal tissue damage is discussed. Experiments to test the validity of this type of model are suggested.

Cell Line↗

Modelling the effect of specific inositol 1,4,5-trisphosphate receptor isoforms on cellular Ca2+ signals.

BACKGROUND INFORMATION: Oscillations of cytosolic Ca2+ are well-known to rely on the regulatory properties of the InsP3R (inositol 1,4,5-trisphosphate receptor). Three isoforms of this channel have been identified. They differ in their regulatory properties by Ca2+ and InsP3. Experiments in different cell types clearly indicate that the relative amounts of each isoform affect the time course of Ca2+ changes after agonist stimulation. In the present study, we investigate whether different steady-state curves for the open probability of the InsP3Rs as a function of Ca2+ imply different dynamical behaviours when these receptors are present in a cellular environment. We therefore describe by a specific phenomenological model the three main types of curves that have been reported: (i) the classical bell-shaped curve, (ii) the bell-shaped curve that is shifted towards higher Ca2+ concentrations when InsP3 is increased, and (iii) a monotonous increasing function of cytosolic Ca2+. RESULTS: We show that, although these types of curves can be ascribed to slight differences in the channel regulation by Ca2+ and InsP3, they can indicate important variations as to the receptor role in cellular Ca2+ control. Thus the receptor associated with the classical bell-shaped curve appears to be the most robust Ca2+ oscillator. If the steady-state curve is supposed to be a monotonous increasing function of cytosolic Ca2+, the modelled receptor cannot sustain Ca2+ oscillations in the absence of Ca2+ exchanges with the extracellular medium. When the bell-shaped curve is shifted towards higher Ca2+ concentrations with increasing InsP3 levels, the model predicts that the receptor is less robust to changes in density; this receptor, however, provides a finer control of the steady-state level of Ca2+ when varying the InsP3 concentration. CONCLUSIONS: Our model allows us to propose an explanation for the experimental observations about the effect of selectively expressing or down-regulating InsP3R isoforms, as well as to make theoretical predictions.

Animals↗

Epidemic outbreaks on structured populations.

Our chances to halt epidemic outbreaks rely on how accurately we represent the population structure underlying the disease spread. When analysing global epidemics this force us to consider metapopulation models taking into account intra- and inter-community interactions. Here I introduce and analyze a metapopulation model which accounts for several features observed in real outbreaks. First, I demonstrate that depending on the intra-community expected outbreak size and the fraction of social bridges the epidemic outbreaks die out or there is a finite probability to observe a global epidemics. Second, I show that the global scenario is characterized by resurgent epidemics, their number increasing with increasing the intra-community average distance between individuals. Finally, I present empirical data for the AIDS epidemics supporting the model predictions.

Acquired Immunodeficiency Syndrome↗

Personal models of diabetes among older adults: relationship to self-management and other variables.

The purpose of this study was to test whether older patients' personal models of diabetes predict their levels of self-management activities (dietary intake, physical activity, and blood glucose testing) and glycemic control. The Personal Models of Diabetes Interview (PMDI) was administered on two occasions to 78 patients (> or = 60 years) with non-insulin-dependent diabetes mellitus. Self-management behaviors, quality of life, and affect were assessed on the second occasion and at 4 months. Glycemic control was assessed at 4 months. Three constructs of the PMDI (cause, treatment effectiveness, and seriousness) were correlated significantly with several aspects of quality of life and with negative affect. Personal models, especially beliefs regarding treatment effectiveness, were predictive of dietary intake and physical activity but not blood glucose testing. Assessing patients' personal models is valuable for individualizing education and counseling for nutrition and physical activity, and selecting strategies consistent with patients' perspectives.

Aged↗

Predictors of depressive symptoms in older people--a survey of two general practice populations.

BACKGROUND: Studies have shown strong associations between disability, social support and depressive symptoms in older people; but socio-economic effects are less clear and little is known about the role of health locus of control. OBJECTIVE: To examine the roles of physical health, disability, social support, socio-economic factors and health locus of control as predictors of depressive symptoms in older people. METHOD: A postal survey of patients aged >/= 65 years from two London practices. Outcome measure was a score of > 5 on the 15-item Geriatric Depression Scale. Associations with other factors were examined using logistic regression and expressed as odds ratios. RESULTS: 70.4% (1602/2276) responded and provided Geriatric Depression Score 15 data, with 23.8% (381/1602) scoring > 5. After adjusting for age, sex and practice, high depression scores were associated with: (i) physical health and disability [e.g. severe versus no disability odds ratio 26.9 (15.7-46.2)]; (ii) social support [e.g. dissatisfaction with support odds ratio 4.2 (3.2-5.6)]; (iii) socio-economic [e.g. no occupational pension odds ratio 1.9 (1.5-2.4)]; (iv) health locus of control [e.g. internality 0.6 (0.6-0.7)]. After adjusting for disability, associations with general measures of physical health were reduced but still significant, while associations with social support, socio-economic factors, and health locus of control were unaffected. All four groups of factors were included in a final model for predicting depressive symptoms. CONCLUSIONS: Disability, physical health, social support, socio-economic factors, and health locus of control were all independent depression score predictors in this study. This has implications for measures to reduce depressive symptoms in older people.

Aged↗

Analyzing predictive models following definitive radiotherapy for prostate carcinoma.

BACKGROUND: As we approach the 21st century, clinically useful predictive models for prostate carcinoma are urgently needed to stratify patients reliably for future treatment strategies. Recently, many investigators have developed models that employ prostate specific antigen (PSA)-based constructs or groupings in an attempt to predict outcome accurately following definitive radiotherapy. This investigation was conducted to determine which of these models provides the closest "fit" to independent clinical outcome data measuring biochemical freedom from failure (bNED control), thereby warranting further exploration. METHODS: Six models were analyzed in a definitive radiotherapy series of 421 patients with localized prostate carcinoma treated with a median dose of 74 Gray (Gy) between March 1988 and November 1994. A stepwise Cox proportional hazards multivariate analysis (MVA) was performed to predict for bNED control using the following covariates: PSA, Gleason's score, stage, dose, PSA density, and perineural invasion. Subsequent MVAs were performed for each model incorporating the new construct or prognostic groupings. The adequacy of the models was confirmed using plots of score residuals against time to bNED failure and comparisons were made used Akaike's Information Criteria (AIC) in which a smaller value corresponds to a statistically improved model based on explained variation and the number of predictors. Because PSA was distributed in a log-normal fashion in the current study population, the model-building process was duplicated using a logarithmic transformation analysis. Biochemical failure was defined as 2 consecutive elevations in the PSA > or = 1.5 ng/mL. The median follow-up time was 34 months (range, 2-87 months). RESULTS: Initially, the model developed by Pisansky et al. appeared the most predictive due to the parsimony in their risk estimate, which is the sole predictor of outcome, as well as its associated lowest AIC value. However, after the logarithmic transformation analysis, all the models appeared to be equally predictive of bNED outcome. CONCLUSIONS: A plethora of accurate models for predicting outcome following definitive radiotherapy for prostate carcinoma recently have been engineered, all of which are essentially equally predictive in this data base (via a logarithmic conversion process). This analysis should be corroborated in other large radiotherapy series.

Follow-Up Studies↗

Cognitive restructuring in the treatment of social phobia. Efficacy and mode of action.

Cognitive restructuring (CR) is commonly used to treat social phobia, although its contribution to treatment efficacy has not been established. CR requires the person to think about and discuss feared social events with his or her therapist and thus entails some degree of exposure to social stimuli. CR also is thought to enhance the efficacy of therapeutic exposure exercises (EXP). Four predictions were tested based on this model: Relative to a control intervention matched for the exposure inherent in CR, CR is more effective in (1) reducing social phobia, (2) reducing negative social cognitions, (3) increasing positive cognitions, and (4) enhancing the effects of subsequent EXP. People with generalized social phobia (N = 60) were randomly assigned to CR followed by EXP or to a control intervention followed by EXP. Support was found for predictions 1 to 3, but not 4.

Adult↗

A mathematical model of the pancreatic ductal epithelium.

A mathematical model of the HCO-3-secreting pancreatic ductal epithelium was developed using network thermodynamics. With a minimal set of assumptions, the model accurately reproduced the experimentally measured membrane potentials, voltage divider ratio, transepithelial resistance and short-circuit current of nonstimulated ducts that were microperfused and bathed with a CO2/HCO-3-free, HEPES-buffered solution, and also the intracellular pH of duct cells bathed in a CO2/HCO-3-buffered solution. The model also accurately simulated: (i) the effect of step changes in basolateral K+ concentration, and the effect of K+ channel blockers on basolateral membrane potential; (ii) the intracellular acidification caused by a Na+-free extracellular solution and the effect of amiloride on this acidification; and (iii) the intracellular alkalinization caused by a Cl--free extracellular solution and the effect of DIDS on this alkalinization. In addition, the model predicted that the luminal Cl- conductance plays a key role in controlling both the HCO-3 secretory rate and intracellular pH during HCO-3 secretion. We believe that the model will be helpful in the analysis of experimental data and improve our understanding of HCO-3-transporting mechanisms in pancreatic duct cells.

Animals↗

Air emission flux from contaminated dredged materials stored in a pilot-scale confined disposal facility.

A pilot-scale field simulation was conducted to estimate the air emissions from contaminated dredged material stored in a confined disposal facility (CDF). Contaminated dredged material with a variety of organic chemicals, obtained from Indiana Harbor Canal, was used in the study. It was placed in an outdoor CDF simulator (i.e., a lysimeter of dimensions 4 ft x 4 ft x 2 ft). A portable, dynamic flux chamber was used to periodically measure emissions of various polynuclear aromatic hydrocarbons (PAHs). A weather station was set up to monitor and record the meteorological conditions during the experiment. The fluxes of several PAHs were monitored over time for 6 1/2 months. Initial 6-hr average fluxes varied from 2 to 20 ng/cm2/hr for six different PAHs. The flux values declined rapidly for all compounds soon after placement of the dredged material in the CDE Chemical concentrations derived from flux values were generally of low magnitude compared with ambient standards. Data obtained from the experiment were compared against those predicted using models for air emissions. Model simulations showed that initially the flux was largely from exposed pore water from saturated (wet) sediment, whereas the long-term flux was controlled by diffusion through the pore air of the unsaturated sediment. Model predictions generally overestimated the measured emissions. A rainfall event was simulated, and the dredged material was reworked to simulate that typical of a CDF operation. Increased flux was observed upon reworking the dredged material.

Air Pollutants↗

A mathematical analysis for the cardiovascular control adaptations in chronic renal failure.

A model of baroreflex control of blood pressure (BP) is proposed in terms of a delay differential equation and this is used to predict the adaptation of short-term cardiovascular control in chronic renal failure (CRF) patients. Cardiac pump dynamics are explored by means of plots of blood flow vs. mean BP. The parameters of the model were determined from available data and from a sensitivity analysis. The model predicts stable and unstable equilibria close to the steady BP. It is shown that the unstable equilibrium point generates a quasiperiodic solution with two main harmonics for healthy subjects. We also show that the parameters for CRF patients predict solutions whose spectra exhibit a small high frequency component. This is due to the coalescence of the equilibrium points. The heart rate variability (HRV) time series and power spectra from healthy volunteers and CRF patients were compared with the model predictions. As an adequate measure of the sympathovagal balance we use the LF/HF index obtained from the power spectrum. The model allows the interpretation of the variability of the LF/HF index in terms of a specific set of cardiovascular parameters which are known to change from healthy to CRF patients. Comparisons of the changes in the LF/HF index predicted by the model are in agreement with actual observations for both the healthy and the CRF patients. These results show that the cardiac pump has a more restricted response in CRF patients. The model quantifies the cardiovascular adaptations to the CRF condition in terms of increased peripheral resistance and baroreflex delay and decreased arterial compliance, cardiac period, and stroke volume.

Adaptation, Physiological↗

Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients.

PURPOSE: To develop clinical prediction models for local regional recurrence (LRR) of breast carcinoma after mastectomy that will be superior to the conventional measures of tumor size and nodal status. METHODS AND MATERIALS: Clinical information from 1,010 invasive breast cancer patients who had primary modified radical mastectomy formed the database of the training and testing of clinical prognostic and prediction models of LRR. Cox proportional hazards analysis and Bayesian tree analysis were the core methodologies from which these models were built. To generate a prognostic index model, 15 clinical variables were examined for their impact on LRR. Patients were stratified by lymph node involvement (<4 vs. >or =4) and local regional status (recurrent vs. control) and then, within strata, randomly split into training and test data sets of equal size. To establish prediction tree models, 255 patients were selected by the criteria of having had LRR (53 patients) or no evidence of LRR without postmastectomy radiotherapy (PMRT) (202 patients). RESULTS: With these models, patients can be divided into low-, intermediate-, and high-risk groups on the basis of axillary nodal status, estrogen receptor status, lymphovascular invasion, and age at diagnosis. In the low-risk group, there is no influence of PMRT on either LRR or survival. For intermediate-risk patients, PMRT improves LR control but not metastases-free or overall survival. For the high-risk patients, however, PMRT improves both LR control and metastasis-free and overall survival. CONCLUSION: The prognostic score and predictive index are useful methods to estimate the risk of LRR in breast cancer patients after mastectomy and for estimating the potential benefits of PMRT. These models provide additional information criteria for selection of patients for PMRT, compared with the traditional selection criteria of nodal status and tumor size.

Adult↗

Modelling the epidemiology, transmission and control of lymphatic filariasis.

Wuchereria bancrofti transmitted by Culex quinquefasciatus accounts for >90% of the global burden of lymphatic filariasis (LF). Recent advances in diagnostic and control tools and a better epidemiological understanding of the disease have led to hope that LF is eradicable. The World Health Organization has helped a number of member countries to launch nation-wide programmes of mass treatment with antifilarial drugs such as diethylcarbamazine, albendazole and ivermectin, for the elimination of this disease. In order to make rational decisions about control strategies, reliable predictions of the long-term impact of such treatment, and of alternative interventions, need to be made, and these can only be based on a sound, quantitative understanding of the population biology of the parasites. Mathematical models have proven valuable in gaining quantitative insights into the population dynamics of the parasites, and may be used to make credible predictions of the likely outcomes of various control strategies. This article provides an overview of the development of the relevant mathematical/statistical models and of their application in studies of the epidemiology, transmission and control of lymphatic filariasis.

Animals↗