Using the effect size to model change in preference values from descriptive health status

Objectives: This pilot study describes a modelling approach to translate group-level changes in health status into changes in preference values, by using the effect size (ES) to summarize group-level improvement. Methods: ESs are the standardized mean difference between treatment groups in standard deviation (SD) units. Vignettes depicting varying severity in SD decrements on the SF-12 mental health summary scale, with corresponding symptom severity profiles, were valued by a convenience sample of general practitioners (n = 42) using the rating scale (RS) and time trade-off methods. Translation factors between ES differences and change in preference value were developed for five mental disorders, such that ES from published meta-analyses could be transformed into predicted changes in preference values. Results: An ES difference in health status was associated with an average 0.171-0.204 difference in preference value using the RS, and 0.104-0.158 using the time trade off. Conclusions: This observed relationship may be particular to the specific versions of the measures employed in the present study. With further development using different raters and preference measures, this approach may expand the evidence base available for modelling preference change for economic analyses from existing data.

Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

Validation of a food-frequency questionnaire assessment of carotenoid and vitamin E intake using weighed food records and plasma biomarkers: The method of triads model

Background: Reliability or validity studies are important for the evaluation of measurement error in dietary assessment methods. An approach to validation known as the method of triads uses triangulation techniques to calculate the validity coefficient of a food-frequency questionnaire (FFQ). Objective: To assess the validity of an FFQ estimates of carotenoid and vitamin E intake against serum biomarker measurements and weighed food records (WFRs), by applying the method of triads. Design: The study population was a sub-sample of adult participants in a randomised controlled trial of beta-carotene and sunscreen in the prevention of skin cancer. Dietary intake was assessed by a self-administered FFQ and a WFR. Nonfasting blood samples were collected and plasma analysed for five carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene) and vitamin E. Correlation coefficients were calculated between each of the dietary methods and the validity coefficient was calculated using the method of triads. The 95% confidence intervals for the validity coefficients were estimated using bootstrap sampling. Results: The validity coefficients of the FFQ were highest for alpha-carotene (0.85) and lycopene (0.62), followed by beta- carotene (0.55) and total carotenoids (0.55), while the lowest validity coefficient was for lutein (0.19). The method of triads could not be used for b- cryptoxanthin and vitamin E, as one of the three underlying correlations was negative. Conclusions: Results were similar to other studies of validity using biomarkers and the method of triads. For many dietary factors, the upper limit of the validity coefficients was less than 0.5 and therefore only strong relationships between dietary exposure and disease will be detected.

Canine model for investigating the impact of oral enrofloxacin on commensal coliforms and colonization with multidrug-resistant Escherichia coli

A model was developed in dogs to determine the impact of oral enrofloxacin administration on the indigenous coliform population in the gastrointestinal tract and subsequent disposition to colonization by a strain of multidrug-resistant Escherichia coli (MDREC). Dogs given a daily oral dose of 5 mg enrofloxacin kg(-1) for 21 consecutive days showed a significant decline in faecal coliforms to levels below detectable limits by 72 In of administration. Subsequently, faecal coliforms remained suppressed throughout the period of enrofloxacin dosing. Upon termination of antibiotic administration, the number of excreted faecal coliforms slowly returned over an 8-day period, to levels comparable to those seen prior to antibiotic treatment. Enrofloxacin-treated dogs were more effectively colonized by MDREC, evidenced by a significantly increased count of MDREC in the faeces (7.1 +/- 1.5 log(10) g(-1)) compared with non-antibiotic-treated dogs (5.2 +/- 1.2; P = 0.003). Furthermore, antibiotic treatment also sustained a significantly longer period of MDREC excretion in the faeces (26.8 +/- 10.5 days) compared with animals not treated with enrofloxacin (8.5 +/- 5.4 days; P = 0.0215). These results confirm the importance of sustained delivery of an antimicrobial agent to maintain and expand the colonization potential of drug-resistant bacteria in vivo, achieved in part by reducing the competing commensal coliforms in the gastrointestinal tract to below detectable levels in the faeces. Without in vivo antimicrobial selection pressure, commensal coliforms dominated the gastrointestinal tract at the expense of the MDREC population. Conceivably, the model developed could be used to test the efficacy of novel non-antibiotic strategies aimed at monitoring and controlling gastrointestinal colonization by multidrug-resistant members of the Enterobacteriaceae that cause nosocomial infections.

Monitoring green turtles (Chelonia mydas) at a coastal foraging area in Baja California, Mexico: multiple indices to describe population status

From June 1995 to August 2002 we assessed green turtle (Chelonia mydas) population structure and survival, and identified human impact, at Bahia de los Angeles, a large bay that was once the site of the greatest sea turtle harvest rates in the Gulf of California, Mexico. Turtles were captured live with entanglement nets and mortality was quantified through stranding surveys and flipper tag recoveries. A total of 14,820 netting hours (617.5 d) resulted in 255 captures of 200 green turtles. Straight-carapace length and mass ranged from 46.0-100.0 cm (mean = 74.3 +/- 0.7 cm) and 14.5-145.0 kg (mean = 61.5 +/- 1.7 kg), respectively. The size-frequency distribution remained stable during all years and among all capture locations. Anthropogenic-derived injuries ranging from missing flippers to boat propeller scars were present in 4% of captured turtles. Remains of 18 turtles were found at dumpsites, nine stranded turtles were encountered in the study area, and flipper tags from seven turtles were recovered. Survival was estimated at 0.58 for juveniles and 0.97 for adults using a joint live-recapture and dead-recovery model (Burnham model). Low survival among juveniles, declining annual catch per unit effort, and the presence of butchered carcasses indicated human activities continue to impact green turtles at this foraging area.

Of sheep and rain: large-scale population dynamics of the red kangaroo

1. We analysed time-series data from populations of red kangaroos (Macropus rufus, Desmarest) inhabiting four areas in the pastoral zone of South Australia. We formulated a set of a priori models to disentangle the relative effects of the covariates: rainfall, harvesting, intraspecific competition, and domestic herbivores, on kangaroo population-growth rate. 2. The statistical framework allowed for spatial variation in the growth-rate parameters, response to covariates, and environmental variability, as well as spatially correlated error terms due to shared environment. 3. The most parsimonious model included all covariates but no area-specific parameter values, suggesting that kangaroo densities respond in the same way to the covariates across the areas. 4. The temporal dynamics were spatially correlated, even after taking into account the potentially synchronizing effect of rainfall, harvesting and domestic herbivores. 5. Counter-intuitively, we found a positive rather than negative effect of domestic herbivore density on the population-growth rate of kangaroos. We hypothesize that this effect is caused by sheep and cattle acting as a surrogate for resource availability beyond rainfall. 6. Even though our system is well studied, we must conclude that approximating resources by surrogates such as rainfall is more difficult than previously thought. This is an important message for studies of consumer-resource systems and highlights the need to be explicit about population processes when analysing population patterns.

Approximating persistence in a general class of population processes

We provide a general framework for estimating persistence in populations which may be affected by catastrophic events, and which are either unbounded or have very large ceilings. We model the population using a birth-death process modified to allow for downward jumps of arbitrary size. For such processes, it is typically necessary to truncate the process in order to make the evaluation of expected extinction times (and higher-order moments) computationally feasible. Hence, we give particular attention to the selection of a cut-off point at which to truncate the process, and we present a simple method for obtaining quantitative indicators of the suitability of a chosen cut-off. (c) 2005 Elsevier Inc. All rights reserved.

Increase of a Caribbean leatherback turtle Dermochelys coriacea nesting population linked to long-term nest protection

The leatherback turtle Dermochelys coriacea is considered to be at serious risk of global extinction, despite ongoing conservation efforts. Intensive long-term monitoring of a leatherback nesting population on Sandy Point (St. Croix, US Virgin Islands) offers a unique opportunity to quantify basic population parameters and evaluate effectiveness of nesting beach conservation practices. We report a significant increase in the number of females nesting annually from ca. 18-30 in the 1980s to 186 in 2001, with a corresponding increase in annual hatchling production from ca. 2000 to over 49,000. We then analyzed resighting data from 1991 to 2001 with an open robust-design capture-mark-recapture model to estimate annual nester survival and adult abundance for this population. The expected annual survival probability was estimated at ca. 0.893 (95% CL 0.87-0.92) and the population was estimated to be increasing ca. 13% pa since the early 1990s. Taken together with DNA fingerprinting that identify mother-daughter relations, our findings suggest that the increase in the size of the nesting population since 1991 was probably due to an aggressive program of beach protection and egg relocation initiated more than 20 years ago. Beach protection and egg relocation provide a simple and effective conservation strategy for this Northern Caribbean nesting population as long as adult survival at sea remains relatively high. (c) 2005 Elsevier Ltd. All rights reserved.

Population pharmacokinetics and association between A77 1726 plasma concentrations and disease activity measures following administration of leflunomide to people with rheumatoid arthritis

Aims To investigate the concentration-effect relationship and pharmacokinetics of leflunomide in patients with rheumatoid arthritis (RA). Methods Data were collected from 23 RA patients on leflunomide therapy (as sole disease modifying antirheumatic drug (DMARD)) for at least 3 months. Main measures were A77 1726 (active metabolite of leflunomide) plasma concentrations and disease activity measures including pain, duration/intensity of morning stiffness, and SF-36 survey. A population estimate was sought for apparent clearance (CL/F ) and volume of distribution was fixed (0.155 l kg(-1)). Factors screened for influence on CL/F were weight, age, gender and estimated creatinine clearance. Results Significantly higher A77 1726 concentrations were seen in patients with less swollen joints and with higher SF-36 mental summary scores than in those with measures indicating more active disease (P < 0.05); concentration-effect trends were seen with five other disease activity measures. Statistical analysis of all disease activity measures showed that mean A77 1726 concentrations in groups with greater control of disease activity were significantly higher than those in whom the measures indicated less desirable control (P < 0.05). There was large between subject variability in the dose-concentration relationship. A steady-state infusion model best described the pharmacokinetic data. Inclusion of age as a covariate decreased interindividual variability (P < 0.01), but this would not be clinically important in terms of dosage changes. Final parameter estimate (% CV interindividual variability) for CL/F was 0.0184 l h(-1) (50%) (95% CI 0.0146, 0.0222). Residual (unexplained) variability (% CV) was 8.5%. Conclusions This study of leflunomide in patients using the drug clinically indicated a concentration-effect relationship. From our data, a plasma A77 1726 concentration of 50 mg l(-1) is more likely to indicate someone with less active disease than is a concentration around 30 mg l(-1). The marked variability in pharmacokinetics suggests a place for individualized dosing of leflunomide in RA therapy.

A simulation model of cereal-legume intercropping systems for semi-arid regions II. Model application

Smallholder farmers in Africa practice traditional cropping techniques such as intercropping. Intercropping is thought to offer higher productivity and resource milisation than sole cropping. In this study, risk associated with maize-bean intercropping was evaluated by quantifying long-term yield in both intercropping and sole cropping in a semi-arid region of South Africa (Bloemfontein, Free State) with reference to rainfall variability. The crop simulation model was run with different cultural practices (planting date and plant density) for 52 summer crop growing seasons (1950/1951-2001/2002). Eighty-one scenarios, consisted of three levels of initial soil water, planting date, maize population, and bean population, were simulated. From the simulation outputs, the total land equivalent ratio (LER) was greater than one. The intercrop (equivalent to sole maize) had greater energy value (EV) than sole beans, and the intercrop (equivalent to sole beans) had greater monetary value (MV) than sole maize. From these results, it can be concluded that maize-bean intercropping is advantageous for this semi-arid region. Soil water at planting was the most important factor of all scenario factors, followed by planting date. Irrigation application at planting, November/December planting and high plant density of maize for EV and beans for MV can be one of the most effective cultural practices in the study region. With regard to rainfall variability, seasonal (October-April) rainfall positively affected EV and MV, but not LER. There was more intercrop production in La Nina years than in El Nino years. Thus, better cultural practices may be selected to maximize maize-bean intercrop yields for specific seasons in the semi-arid region based on the global seasonal outlook. (c) 2004 Elsevier B.V. All rights reserved.

Mentoring for population health in general practice divisions

This paper describes the implementation and evaluation of a three-way model of service development mentoring. This population health mentoring program was funded by the Commonwealth Department of Health and Ageing to enable staff from eight Divisions of General Practice in South Australia to gain a sound understanding of population health concepts relevant to their workplace. The distinguishing features of service development mentoring were that the learning was grounded within an individual's work setting and experience; there was an identified population health problem or issue confronting the Division of General Practice; and there was an expectation of enhanced organisational performance. A formal evaluation found a consensus among all learners that mentoring was a positive and worthwhile experience, where they had achieved what they had set out to do. Mentors found the model of learning agreeable and effective. Division executive officers recognised enhanced skills among their "learner" colleagues, and commented positively on the benefits to their organisations through the development of well researched and relevant projects, with the potential to improve the efficiency of their population health activities.

Some considerations on the design of population pharmacokinetic studies

The goal of this manuscript is to introduce a framework for consideration of designs for population pharmacokinetic orpharmacokinetic-pharmacodynamic studies. A standard one compartment pharmacokinetic model with first-order input and elimination is considered. A series of theoretical designs are considered that explore the influence of optimizing the allocation of sampling times, allocating patients to elementary designs, consideration of sparse sampling and unbalanced designs and also the influence of single vs. multiple dose designs. It was found that what appears to be relatively sparse sampling (less blood samples per patient than the number of fixed effects parameters to estimate) can also be highly informative. Overall, it is evident that exploring the population design space can yield many parsimonious designs that are efficient for parameter estimation and that may not otherwise have been considered without the aid of optimal design theory.

The population pharmacokinetics of citalopram after deliberate self-poisoning: A Bayesian approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration-time data from 53 patients studied after 63 citalopram overdose events (dose range: 20-1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients' dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model's ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose-exposure relationship in the toxicological settings.

Analysis of population pharmacokinetic data using NONMEM and WinBUGS

The aim of this report is to describe the use of WinBUGS for two datasets that arise from typical population pharmacokinetic studies. The first dataset relates to gentamicin concentration-time data that arose as part of routine clinical care of 55 neonates. The second dataset incorporated data from 96 patients receiving enoxaparin. Both datasets were originally analyzed by using NONMEM. In the first instance, although NONMEM provided reasonable estimates of the fixed effects parameters it was unable to provide satisfactory estimates of the between-subject variance. In the second instance, the use of NONMEM resulted in the development of a successful model, albeit with limited available information on the between-subject variability of the pharmacokinetic parameters. WinBUGS was used to develop a model for both of these datasets. Model comparison for the enoxaparin dataset was performed by using the posterior distribution of the log-likelihood and a posterior predictive check. The use of WinBUGS supported the same structural models tried in NONMEM. For the gentamicin dataset a one-compartment model with intravenous infusion was developed, and the population parameters including the full between-subject variance-covariance matrix were available. Analysis of the enoxaparin dataset supported a two compartment model as superior to the one-compartment model, based on the posterior predictive check. Again, the full between-subject variance-covariance matrix parameters were available. Fully Bayesian approaches using MCMC methods, via WinBUGS, can offer added value for analysis of population pharmacokinetic data.

Population pharmacokinetics of metformin in late pregnancy

The pharmacokinetic disposition of metformin in late pregnancy was studied together with the level of fetal exposure at birth. Blood samples were obtained in the third trimester of pregnancy from women with gestational diabetes or type 2 diabetes, 5 had a previous diagnosis of polycystic ovary syndrome. A cord blood sample also was obtained at the delivery of some of these women, and also at delivery of others who had been taking metformin during pregnancy but from whom no blood had been taken. Plasma metformin concentrations were assayed by a new, validated, reverse-phase HPLC method, A 2-compartment, extravascular maternal model with transplacental partitioning of drug to a fetal compartment was fitted to the data. Nonlinear mixed-effects modeling was performed in'NONMEM using FOCE with INTERACTION. Variability was estimated using logarithmic interindividual and additive residual variance models; the covariance between clearance and volume was modeled simultaneously. Mean (range) metformin concentrations in cord plasma and in maternal plasma were 0.81 (range, 0.1-2.6) mg/L and 1.2 (range, 0. 1-2.9) mg/L, respectively. Typical population values (interindividual variability, CV%) for allometrically scaled maternal clearance and volume of distribution were 28 L/h/70 kg (17.1%) and 190 L/70 ka (46.3%), giving a derived population-wide half-life of 5.1 hours. The placental partition coefficient for metformin was 1.07 (36.3%). Neither maternal age nor weight significantly influenced the pharmacokinetics. The variability (SD) of observed concentrations about model-predicted concentrations was 0.32 mg/L. The pharmacokinetics were similar to those in nonpregnant patients and, therefore, no dosage adjustment is warranted. Metformin readily crosses the placenta, exposing the fetus to concentrations approaching those in the maternal circulation. The sequelae to such exposure, ea, effects on neonatal obesity and insulin resistance, remain unknown.