Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

BACKGROUND: Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS: Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS: Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION: Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING: German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Do individual directors matter?

Paper 1: Pilot study of Swiss firms Abstract Using a fixed effects approach, we investigate whether the presence of specific individuals on Swiss firms’ boards affects firm performance and the policy choices they make. We find evidence for a substantial impact of these directors’ presence on their firms. Moreover, the director effects are correlated across policies and performance measures but uncorrelated to the directors’ background. We find these results interesting but conclude that they should to be substantiated on a dataset that is larger and better understood by researchers. Also, further tests are required to rule out methodological concerns. Paper 2: Evidence from the S&P 1,500 Abstract We ask whether directors on corporate boards contribute to firm performance as individuals. From the universe of the S&P 1,500 firms since 1996 we track 2,062 directors who serve on multiple boards over extended periods of time. Our initial findings suggest that the presence of these directors is associated with substantial performance shifts (director fixed effects). Closer examination shows that these effects are statistical artifacts and we conclude that directors are largely fungible. Moreover, we contribute to the discussion of the fixed effects method. In particular, we highlight that the selection of the randomization method is pivotal when generating placebo benchmarks. Paper 3: Robustness, statistical power, and important directors Abstract This article provides a better understanding of Senn’s (2014) findings: The outcome that individual directors are unrelated to firm performance proves robust against different estimation models and testing strategies. By looking at CEOs, the statistical power of the placebo benchmarking test is evaluated. We find that only the stronger tests are able to detect CEO fixed effects. However, these tests are not suitable to analyze directors. The suitable tests would detect director effects if the inter quartile range of the true effects amounted to 3 percentage points ROA. As Senn (2014) finds no such effects for outside directors in general, we focus on groups of particularly important directors (e.g., COBs, non-busy directors, successful directors). Overall, our evidence suggests that the members of these groups are not individually associated with firm performance either. Thus, we confirm that individual directors are largely fungible. If the individual has an effect on performance, it is of small magnitude.

Schools and Housing Markets: An Examination of School Segregation and Performance in Connecticut

This paper examines the relationship between house price levels, school performance, and the racial and ethnic composition of Connecticut school districts between 1995 and 2000. A panel of Connecticut school districts over both time and labor market areas is used to estimate a simultaneous equations model describing the determinants of these variables. Specifically, school district changes in price level, school performance, and racial and ethnic compositions depend upon each other, labor market wide changes in these variables, and the deviation of each school district from the overall metropolitan area. The specification is based on the differencing of dependent variables, as opposed to the use of level or fixed effects models and lagging level variables beyond the period over which change is considered; as a result the model is robust to persistence in the sample. Identification of the simultaneous system arises from the presence of multiple labor market areas in the sample, and the assumption that labor market changes in a variable due not directly influence the allocation of households across towns within a labor market area. We find that towns in labor markets that experience an inflow of minority households have greater increases in percent minority if those towns already ahve a substantial minoritypopulation. We find evidence that this sorting proces is reflected in housing price changes in the low priced segment of the housing market, not in the middle and upper segments.

Which School Attributes Matter? The Influence of School District Performance and Demographic Composition on Property Values

Increasing levels of segregation in American schools raises the question: do home buyers pay for test scores or demographic composition? This paper uses Connecticut panel data spanning eleven years from 1994 to 2004 to ascertain the relationship between property values and explanatory variables that include school district performance and demographic attributes, such as racial and ethnic composition of the student body. Town and census tract fixed effects are included to control for neighborhood unobservables. The effect of changes in school district attributes is also examined over a decade long time frame in order to focus on the effect of long run changes, which are more likely to be capitalized into prices. The study finds strong evidence that increases in percent Hispanic has a negative effect on housing prices in Connecticut, but mixed evidence concerning the impact of test scores on property values. Evidence is also found to suggest that student test scores have increased in importance for explaining housing prices in recent years while the importance of percent Hispanic has declined. Finally, the study finds that estimates of property tax capitalization increase substantially when the analysis focuses on long run changes.

Ramadan school holidays as a natural experiment : impacts of seasonality on school dropout in Bangladesh

In 2000, Ramadan school vacation coincided with the original annual exam period of December in Bangladesh. This forced schools to pre-pone their final exam schedules in November, which was the month before the harvest begins. 'Ramadan 2000' is a natural experiment that reduced the labor demand for children during the exam period. Using household level panel data of 2000 and 2003, and after controlling for various unobservable variations including individual fixed effects, aggregate year effects, and subdistrict-level year effects, this paper finds evidence of statistically significant impact of seasonal labor demand on school dropout in Bangladesh among the children from agricultural households.

How serious is the omission of bilateral tariff rates in gravity?

In this paper, using the worldwide dataset of bilateral tariff rates, we explore how serious the omission of bilateral tariff rates in gravity is. Our findings are as follow. Firstly, the omission of bilateral tariff rates seems not to be so serious in terms of omitted-variable biases because the coefficients for the usual gravity variables do not change before or after their inclusion. Secondly, while the widely-used dummy variable of regional trade agreement could not play an alternative role in place of tariff rates, the inclusion of time-invariant pair fixed effects in addition to the time-variant importer fixed effects and exporter fixed effects accounts for the omission of tariff rates. The inclusion of those fixed effects makes the coefficient for bilateral tariff rates insignificant.

The Risk of Using the Q Heterogeneity Estimator for Software Engineering Experiments

All meta-analyses should include a heterogeneity analysis. Even so, it is not easy to decide whether a set of studies are homogeneous or heterogeneous because of the low statistical power of the statistics used (usually the Q test). Objective: Determine a set of rules enabling SE researchers to find out, based on the characteristics of the experiments to be aggregated, whether or not it is feasible to accurately detect heterogeneity. Method: Evaluate the statistical power of heterogeneity detection methods using a Monte Carlo simulation process. Results: The Q test is not powerful when the meta-analysis contains up to a total of about 200 experimental subjects and the effect size difference is less than 1. Conclusions: The Q test cannot be used as a decision-making criterion for meta-analysis in small sample settings like SE. Random effects models should be used instead of fixed effects models. Caution should be exercised when applying Q test-mediated decomposition into subgroups.

Fiber penetration and copper access regulation

Research question, methodology and messages to take home - Impact of copper (legacy networks)regulation(LLU and bitstream)on NGN adoption - Methodology: fixed effects regression and forecasting with s- curves(logistic) - Key message:(excessive) copper regulation discourages NGN adoption (deployment, investments), in particular an increase ofunbundling access charges and/or a decrease of wholesale access would increase penetration of fibre and cable modem.

Analysis of the impact of globalization and economic growth on food security in developing countries

A pesar de los importantes avances en la reducción del hambre, la seguridad alimentaria continúa siendo un reto de dimensión internacional. La seguridad alimentaria es un concepto amplio y multidimensional, cuyo análisis abarca distintas escalas y horizontes temporales. Dada su complejidad, la identificación de las causas de la inseguridad alimentaria y la priorización de las medias para abordarlas, son dos cuestiones que suscitan un intenso debate en la actualidad. El objetivo de esta tesis es evaluar el impacto de la globalización y el crecimiento económico en la seguridad alimentaria en los países en desarrollo, desde una perspectiva macro y un horizonte temporal a largo plazo. La influencia de la globalización se aborda de una manera secuencial. En primer lugar, se analiza la relación entre la inversión público-privada en infraestructuras y las exportaciones agrarias. A continuación, se estudia el impacto de las exportaciones agrarias en los indicadores de seguridad alimentaria. El estudio del impacto del crecimiento económico aborda los cambios paralelos en la distribución de la renta, y cómo la inequidad influye en el comportamiento de la seguridad alimentaria nacional. Además, se analiza en qué medida el crecimiento económico contribuye a acelerar el proceso de mejora de la seguridad alimentaria. Con el fin de conseguir los objetivos mencionados, se llevan a cabo varios análisis econométricos basados en datos de panel, en el que se combinan datos de corte transversal de 52 países y datos temporales comprendidos en el periodo 1991-2012. Se analizan tanto variables en niveles como variables en tasas de cambio anual. Se aplican los modelos de estimación de efectos variables y efectos fijos, ambos en niveles y en primeras diferencias. La tesis incluye cuatro tipos de modelos econométricos, cada uno de ellos con sus correspondientes pruebas de robustez y especificaciones. Los resultados matizan la importancia de la globalización y el crecimiento económico como mecanismos de mejora de la seguridad alimentaria en los países en desarrollo. Se obtienen dos conclusiones relativas a la globalización. En primer lugar, los resultados sugieren que la promoción de las inversiones privadas en infraestructuras contribuye a aumentar las exportaciones agrarias. En segundo lugar, se observa que las exportaciones agrarias pueden tener un impacto negativo en los indicadores de seguridad alimentaria. La combinación de estas dos conclusiones sugiere que la apertura comercial y financiera no contribuye por sí misma a la mejora de la seguridad alimentaria en los países en desarrollo. La apertura internacional de los países en desarrollo ha de ir acompañada de políticas e inversiones que desarrollen sectores productivos de alto valor añadido, que fortalezcan la economía nacional y reduzcan su dependencia exterior. En relación al crecimiento económico, a pesar del incuestionable hecho de que el crecimiento económico es una condición necesaria para reducir los niveles de subnutrición, no es una condición suficiente. Se han identificado tres estrategias adicionales que han de acompañar al crecimiento económico con el fin de intensificar su impacto positivo sobre la subnutrición. Primero, es necesario que el crecimiento económico sea acompañado de una distribución más equitativa de los ingresos. Segundo, el crecimiento económico ha de reflejarse en un aumento de inversiones en salud, agua y saneamiento y educación. Se observa que, incluso en ausencia de crecimiento económico, mejoras en el acceso a agua potable contribuyen a reducir los niveles de población subnutrida. Tercero, el crecimiento económico sostenible en el largo plazo parece tener un mayor impacto positivo sobre la seguridad alimentaria que el crecimiento económico más volátil o inestable en el corto plazo. La estabilidad macroeconómica se identifica como una condición necesaria para alcanzar una mayor mejora en la seguridad alimentaria, incluso habiéndose mejorado la equidad en la distribución de los ingresos. Por último, la tesis encuentra que los países en desarrollo analizados han experimentado diferentes trayectorias no lineales en su proceso de mejora de sus niveles de subnutrición. Los resultados sugieren que un mayor nivel inicial de subnutrición y el crecimiento económico son responsables de una respuesta más rápida al reto de la mejora de la seguridad alimentaria. ABSTRACT Despite the significant reductions of hunger, food security still remains a global challenge. Food security is a wide concept that embraces multiple dimensions, and has spatial-temporal scales. Because of its complexity, the identification of the drivers underpinning food insecurity and the prioritization of measures to address them are a subject of intensive debate. This thesis attempts to assess the impact of globalization and economic growth on food security in developing countries with a macro level scale (country) and using a long-term approach. The influence of globalization is addressed in a sequential way. First, the impact of public-private investment in infrastructure on agricultural exports in developing countries is analyzed. Secondly, an assessment is conducted to determine the impact of agricultural exports on food security indicators. The impact of economic growth focuses on the parallel changes in income inequality and how the income distribution influences countries' food security performance. Furthermore, the thesis analyzes to what extent economic growth helps accelerating food security improvements. To address the above mentioned goals, various econometric models are formulated. Models use panel data procedures combining cross-sectional data of 52 countries and time series data from 1991 to 2012. Yearly data are expressed both in levels and in changes. The estimation models applied are random effects estimation and fixed effects estimations, both in levels and in first differences. The thesis includes four families of econometric models, each with its own set of robustness checks and specifications. The results qualify the relevance of globalization and economic growth as enabling mechanisms for improving food security in developing countries. Concerning globalization, two main conclusions can be drawn. First, results showed that enhancing foreign private investment in infrastructures contributes to increase agricultural exports. Second, agricultural exports appear to have a negative impact on national food security indicators. These two conclusions suggest that trade and financial openness per se do not contribute directly to improve food security in development countries. Both measures should be accompanied by investments and policies to support the development of national high value productive sectors, to strengthen the domestic economy and reduce its external dependency. Referring to economic growth, despite the unquestionable fact that income growth is a pre-requisite for reducing undernourishment, results suggest that it is a necessary but not a sufficient condition. Three additional strategies should accompany economic growth to intensifying its impact on food security. Firstly, it is necessary that income growth should be accompanied by a better distribution of income. Secondly, income growth needs to be followed by investments and policies in health, sanitation and education to improve food security. Even if economic growth falters, sustained improvements in the access to drinking water may still give rise to reductions in the percentage of undernourished people. And thirdly, long-term economic growth appears to have a greater impact on reducing hunger than growth regimes that combine periods of growth peaks followed by troughs. Macroeconomic stability is a necessary condition for accelerating food security. Finally, the thesis finds that the developing countries analyzed have experienced different non-linear paths toward improving food security. Results also show that a higher initial level of undernourishment and economic growth result in a faster response for improving food security.

Efeito da suplementação prolongada de grão de soja cru e integral no pré-parto sobre o desempenho produtivo, qualidade oocitária e embrionária, e função imune de vacas leiteiras

Objetivou-se avaliar o efeito da suplementação prolongada de grão de soja cru e integral (GSI) como fonte de ácido graxo Ω6 sobre o desempenho produtivo, perfil metabólico, qualidade oocitária e embrionária e função imune de vacas leiteiras no período de transição e início de lactação. Foram selecionadas 44 vacas da raça Holandesa, multíparas e gestantes, com parto previsto para 90 dias após o início da avaliação e fornecimento das dietas experimentais, porém em razão da ocorrência de enfermidades metabólicas ou infecciosas (3 abortos; 3 deslocamentos de abomaso; 3 enfermidades podais; 4 distocias) 13 animais foram retirados do experimento. As vacas foram distribuídas aleatoriamente em quatro grupos experimentais diferindo entre eles o início do fornecimento de grão de soja cru e integral (GSI) durante o pré-parto. A dieta era baseada na inclusão de 12% de GSI %MS, com aproximadamente 5,1% de extrato etéreo (EE) o início de seu fornecimento foi conforme descrito a seguir: Grupo 0: Animais não receberam dieta contendo GSI no pré-parto; Grupo 30: Início do fornecimento de dieta com GSI nos 30 dias finais da gestação; Grupo 60: Início do fornecimento de dieta com GSI nos 60 dias finais da gestação; Grupo 90: Início do fornecimento de dieta com GSI nos 90 dias finais da gestação. Após o parto, todas as vacas receberam dieta única com 5,1% de EE, baseada na inclusão de 12% de GSI %MS até 90 dias de lactação. Os animais foram arraçoados de acordo com o consumo de matéria seca no dia anterior, de forma a ser mantido porcentual de sobras das dietas, diariamente, entre 5 e 10%. As amostras dos alimentos e sobras foram coletadas diariamente e armazenadas a -20ºC. Semanalmente as amostras coletadas diariamente foram misturadas e foi retirada uma amostra composta referente a um período de uma semana, a fim de mensurar o consumo de matéria seca e nutrientes. Amostras de fezes foram coletadas nos dias -56, -21, 21, 56 e 84 dias em relação ao parto, com o propósito de mensurar a digestibilidade da matéria seca e nutrientes. A produção de leite foi mensurada diariamente e para a composição dos teores de gordura, proteína, lactose e perfil de ácidos graxos amostras foram coletadas semanalmente. As amostras de sangue para análise dos metabólitos sanguíneos foram coletadas semanalmente. Amostras de sangue para mensurar a atividade do sistema imune foram coletadas na semanas -8, -4, -2, -1 em relação ao parto, parto, +1, +2, +4 e +8 semanas no período pós-parto. Nos dias 21, 42, 63 e 84 do período pós-parto foram realizadas aspirações foliculares, com posterior fertilização in vitro dos oócitos. Todas as variáveis mensuradas foram analisadas pelo procedimento PROC MIXED do SAS 9.4 através de regressão polinomial, utilizando efeito fixo de tratamento, semana, interação tratamento*semana e efeito de animal dentro de tratamento como aleatório. Utilizou nível de 5% de significância. Foi observado efeito (P<0,05) linear crescente para CEE no pré-parto. Não foi observado diferenças no CMS e nutrientes no pós-parto. Não houve alteração da digestibilidade nos períodos pré e pós-parto. Não houve alteração no balanço de energia e nitrogênio nos periodos pré e pós-parto. Não foi observado diferença na produção, composição e teor dos componentes totais do leite. No perfil de ácidos graxos do leite houve efeito (P<0,05) linear descrescente para as concentrações de C16:1cis, C18:1 cis, total de C:18 insaturado, total de AG monoinsaturados, insaturados e a relação do total de AGS:AGI. Foi observado efeito linear (P<0,05) crescente para o total de AG aturado e efeito (P<0,05) quadrático para C18:2, CLAcis9-trans11, e total de AGPI. Foi observado efeito linear crescente (P<0,05) para colesterol total, LDL no préparto e linear decrescente (P<0,05) para GGT nos períodos pré e pós-parto. Foi observado efeito quadrático (P<0,05) para HDL no pré-parto e AST no pós-parto. Em relação a atividade do sistema imune foi observado efeito linear (P<0,05) crescente para o percentual de CD3+ ativos no pós-parto, para o percentual de monócitos que produziram espécie reativa de oxigênio (ERO) no pós-parto quando foram estimulados por S.aureus e E.coli e para a intensidade de imunofluorescência de ERO para ganulócitos no pós-parto quando estimulados por S.aureus. Foi observado efeito (P<0,05) quadrático para o percentual de granulócitos, mononucleares, CD8+ ativos no pós-parto e para o percentual de granulócitos que produziram ERO no pós-parto quando estimulados por E.coli. A suplementação prolongada com GSI no pré-parto melhora a atividade do sistema imune, não melhora a qualidade oocitária e embrionária bem como não influencia negativamente os parametros produtivos de vacas leiteiras no período de transição e início de lactação

Do agricultural subsidies crowd out or stimulate rural credit institutions? The Case of CAP Payments. Factor Markets Working Paper No. 4, September 2011

In this paper we estimate the impact of subsidies from the EU’s common agricultural policy on farm bank loans. According to the theoretical results, if subsidies are paid at the beginning of the growing season they may reduce bank loans, whereas if they are paid at the end of the season they increase bank loans, but these results are conditional on whether farms are credit constrained and on the relative cost of internal and external financing. In the empirical analysis, we use farm-level panel data from the Farm Accountancy Data Network to test the theoretical predictions for the period 1995–2007. We employ fixed-effects and generalised method of moment models to estimate the impact of subsidies on farm loans. The results suggest that subsidies influence farm loans and the effects tend to be non-linear and indirect. The results also indicate that both coupled and decoupled subsidies stimulate long-term loans, but the long-term loans of large farms increase more than those of small farms, owing to decoupled subsidies. Furthermore, the results imply that short-term loans are affected only by decoupled subsidies, and they are altered by decoupled subsidies more for small farms than for large farms; however, when controlling for endogeneity, only the decoupled payments affect loans and the relationship is non-linear.

Governança corporativa e custo de agência: uma visão do mercado brasileiro

Esse trabalho investiga empiricamente a relação entre custo de agência e as medidas de monitoramento interno disponíveis aos investidores brasileiros nas empresas nacionais, utilizando amostras de companhias abertas entre os anos de 2010 e 2014, totalizando 134 empresas analisadas e 536 observações. Para medir tal relação, foram utilizadas, como variáveis de monitoramento interno, informações sobre a remuneração variável dos executivos, entre elas o uso de outorgas de opções de compra de ações, a composição do conselho de administração, dando ênfase à representatividade dos conselheiros independentes e à dualidade entre Chairman e CEO, e o percentual do capital social das companhias que está sob propriedade dos executivos. Como proxy para custo de agência, foram utilizados os indicadores Asset Turnover Ratio e General & Administrative Expenses (G&A) como percentual da Receita Líquida. Neste contexto, foram estabelecidas duas hipóteses de pesquisa e estimados modelos de regressão em painel controlados por efeitos fixos de tempo e empresa, empregando como variável dependente as variáveis proxy do custo de agência e utilizando as variáveis endividamento e tamanho das empresas como variáveis de controle. Os resultados dos modelos demonstram que, na amostra selecionada, há uma relação positiva e significativa entre o percentual da remuneração variável e as proxies de custo de agência, comportamento este contrário ao esperado originalmente. Conclui-se assim que as empresas que apresentam uma maior composição variável no total remunerado ao executivo, incorrem em um maior custo de agência, o que leva à conclusão de que tais ferramentas não são boas estratégias de alinhamento de interesses entre executivos e acionistas. As demais variáveis de monitoramento interno não apresentaram significância.

Modelling the effect of fibropapilloma disease on the somatic growth dynamics of Hawaiian green sea turtles

The effect of the tumour-forming disease, fibropapillomatosis, on the somatic growth dynamics of green turtles resident in the Pala'au foraging grounds (Moloka'i, Hawai'i) was evaluated using a Bayesian generalised additive mixed modelling approach. This regression model enabled us to account for fixed effects (fibropapilloma tumour severity), nonlinear covariate functional form (carapace size, sampling year) as well as random effects due to individual heterogeneity and correlation between repeated growth measurements on some turtles. Somatic growth rates were found to be nonlinear functions of carapace size and sampling year but were not a function of low-to-moderate tumour severity. On the other hand, growth rates were significantly lower for turtles with advanced fibropapillomatosis, which suggests a limited or threshold-specific disease effect. However, tumour severity was an increasing function of carapace size-larger turtles tended to have higher tumour severity scores, presumably due to longer exposure of larger (older) turtles to the factors that cause the disease. Hence turtles with advanced fibropapillomatosis tended to be the larger turtles, which confounds size and tumour severity in this study. But somatic growth rates for the Pala'au population have also declined since the mid-1980s (sampling year effect) while disease prevalence and severity increased from the mid-1980s before levelling off by the mid-1990s. It is unlikely that this decline was related to the increasing tumour severity because growth rates have also declined over the last 10-20 years for other green turtle populations resident in Hawaiian waters that have low or no disease prevalence. The declining somatic growth rate trends evident in the Hawaiian stock are more likely a density-dependent effect caused by a dramatic increase in abundance by this once-seriously-depleted stock since the mid-1980s. So despite increasing fibropapillomatosis risk over the last 20 years, only a limited effect on somatic growth dynamics was apparent and the Hawaiian green turtle stock continues to increase in abundance.

A Bayesian approach to imposing curvature on distance functions

The estimated parameters of output distance functions frequently violate the monotonicity, quasi-convexity and convexity constraints implied by economic theory, leading to estimated elasticities and shadow prices that are incorrectly signed, and ultimately to perverse conclusions concerning the effects of input and output changes on productivity growth and relative efficiency levels. We show how a Bayesian approach can be used to impose these constraints on the parameters of a translog output distance function. Implementing the approach involves the use of a Gibbs sampler with data augmentation. A Metropolis-Hastings algorithm is also used within the Gibbs to simulate observations from truncated pdfs. Our methods are developed for the case where panel data is available and technical inefficiency effects are assumed to be time-invariant. Two models-a fixed effects model and a random effects model-are developed and applied to panel data on 17 European railways. We observe significant changes in estimated elasticities and shadow price ratios when regularity restrictions are imposed. (c) 2004 Elsevier B.V. All rights reserved.

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.