Fitting models for the joint action of two drugs using SAS(R)

Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of synergism, in which the joint action is greater than the actions of the individual drugs, or of antagonism, in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study. Copyright © 2007 John Wiley & Sons, Ltd.

A micro-level simulation for the prediction of intention and behaviour

In this contribution we aim at anchoring Agent-Based Modeling (ABM) simulations in actual models of human psychology. More specifically, we apply unidirectional ABM to social psychological models using low level agents (i.e., intra-individual) to examine whether they generate better predictions, in comparison to standard statistical approaches, concerning the intentions of performing a behavior and the behavior. Moreover, this contribution tests to what extent the predictive validity of models of attitude such as the Theory of Planned Behavior (TPB) or Model of Goal-directed Behavior (MGB) depends on the assumption that peoples’ decisions and actions are purely rational. Simulations were therefore run by considering different deviations from rationality of the agents with a trembling hand method. Two data sets concerning respectively the consumption of soft drinks and physical activity were used. Three key findings emerged from the simulations. First, compared to standard statistical approach the agent-based simulation generally improves the prediction of behavior from intention. Second, the improvement in prediction is inversely proportional to the complexity of the underlying theoretical model. Finally, the introduction of varying degrees of deviation from rationality in agents’ behavior can lead to an improvement in the goodness of fit of the simulations. By demonstrating the potential of ABM as a complementary perspective to evaluating social psychological models, this contribution underlines the necessity of better defining agents in terms of psychological processes before examining higher levels such as the interactions between individuals.

Changing direction on direction of fit

In this paper, I show that we should understand the direction of fit of beliefs and desires in normative terms. After rehearsing a standard objection to Michael Smith’s analysis of direction of fit, I raise a similar problem for Lloyd Humberstone’s analysis. I go on to offer my own account, according to which the difference between beliefs and desires is determined by the normative relations such states stand in. I argue that beliefs are states which we have reason to change in light of the world, whereas desires are states that give us reason to change the world. After doing this, I show how the view avoids various objections, including two from David Sobel and David Copp. The paper ends by briefly discussing the relevance of the view to the Humean theory of motivation.

On reliability analysis of multi-categorical forecasts

Reliability analysis of probabilistic forecasts, in particular through the rank histogram or Talagrand diagram, is revisited. Two shortcomings are pointed out: Firstly, a uniform rank histogram is but a necessary condition for reliability. Secondly, if the forecast is assumed to be reliable, an indication is needed how far a histogram is expected to deviate from uniformity merely due to randomness. Concerning the first shortcoming, it is suggested that forecasts be grouped or stratified along suitable criteria, and that reliability is analyzed individually for each forecast stratum. A reliable forecast should have uniform histograms for all individual forecast strata, not only for all forecasts as a whole. As to the second shortcoming, instead of the observed frequencies, the probability of the observed frequency is plotted, providing and indication of the likelihood of the result under the hypothesis that the forecast is reliable. Furthermore, a Goodness-Of-Fit statistic is discussed which is essentially the reliability term of the Ignorance score. The discussed tools are applied to medium range forecasts for 2 m-temperature anomalies at several locations and lead times. The forecasts are stratified along the expected ranked probability score. Those forecasts which feature a high expected score turn out to be particularly unreliable.

Evaluating the Bank of England density forecasts of inflation

We consider evaluating the UK Monetary Policy Committee's inflation density forecasts using probability integral transform goodness-of-fit tests. These tests evaluate the whole forecast density. We also consider whether the probabilities assigned to inflation being in certain ranges are well calibrated, where the ranges are chosen to be those of particular relevance to the MPC, given its remit of maintaining inflation rates in a band around per annum. Finally, we discuss the decision-based approach to forecast evaluation in relation to the MPC forecasts

The pitfalls of ecological forecasting

Ecological forecasting is difficult but essential, because reactive management results in corrective actions that are often too late to avert significant environmental damage. Here, we appraise different forecasting methods with a particular focus on the modelling of species populations. We show how simple extrapolation of current trends in state is often inadequate because environmental drivers change in intensity over time and new drivers emerge. However, statistical models, incorporating relationships with drivers, simply offset the prediction problem, requiring us to forecast how the drivers will themselves change over time. Some authors approach this problem by focusing in detail on a single driver, whilst others use ‘storyline’ scenarios, which consider projected changes in a wide range of different drivers. We explain why both approaches are problematic and identify a compromise to model key drivers and interactions along with possible response options to help inform environmental management. We also highlight the crucial role of validation of forecasts using independent data. Although these issues are relevant for all types of ecological forecasting, we provide examples based on forecasts for populations of UK butterflies. We show how a high goodness-of-fit for models used to calibrate data is not sufficient for good forecasting. Long-term biological recording schemes rather than experiments will often provide data for ecological forecasting and validation because these schemes allow capture of landscape-scale land-use effects and their interactions with other drivers.

Assessment and improvement of biotransfer models to cow’s milk and beef used in exposure assessment tools for organic pollutants

The aim of this study was to assess and improve the accuracy of biotransfer models for the organic pollutants (PCBs, PCDD/Fs, PBDEs, PFCAs, and pesticides) into cow’s milk and beef used in human exposure assessment. Metabolic rate in cattle is known as a key parameter for this biotransfer, however few experimental data and no simulation methods are currently available. In this research, metabolic rate was estimated using existing QSAR biodegradation models of microorganisms (BioWIN) and fish (EPI-HL and IFS-HL). This simulated metabolic rate was then incorporated into the mechanistic cattle biotransfer models (RAIDAR, ACC-HUMAN, OMEGA, and CKow). The goodness of fit tests showed that RAIDAR, ACC-HUMAN, OMEGA model performances were significantly improved using either of the QSARs when comparing the new model outputs to observed data. The CKow model is the only one that separates the processes in the gut and liver. This model showed the lowest residual error of all the models tested when the BioWIN model was used to represent the ruminant metabolic process in the gut and the two fish QSARs were used to represent the metabolic process in the liver. Our testing included EUSES and CalTOX which are KOW-regression models that are widely used in regulatory assessment. New regressions based on the simulated rate of the two metabolic processes are also proposed as an alternative to KOW-regression models for a screening risk assessment. The modified CKow model is more physiologically realistic, but has equivalent usability to existing KOW-regression models for estimating cattle biotransfer of organic pollutants.

Solvatochromism in Binary Mixtures: First Report on a Solvation Free Energy Relationship between Solvent Exchange Equilibrium Constants and the Properties of the Medium

We have employed UV-vis spectroscopy in order to investigate details of the solvation of six solvatochromic indicators, hereafter designated as ""probes"", namely, 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (RB); 4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePM; 1-methylquinolinium-8-olate, QB; 2-bromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr, 2,6-dichloro-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (WB); and 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr,, respectively. These can be divided into three pairs, each includes two probes of similar pK(a) in water and different lipophilicity. Solvation has been studied in binary mixtures, BMs, of water, W, with 12 protic organic solvents, S, including mono- and bifunctional alcohols (2-alkoxyethanoles, unsaturated and chlorinated alcohols). Each medium was treated as a mixture of S, W, and a complex solvent, S-W, formed by hydrogen bonding. Values of lambda(max) (of the probe intramolecular charge transfer) were converted into empirical polarity scales, E(T)(probe) in kcal/mol, whose values were correlated with the effective mole fraction of water in the medium, chi w(effective). This correlation furnished three equilibrium constants for the exchange of solvents in the probe solvation shell; phi(W/S) (W substitutes S): phi(S-W/W) (S-W substitutes W), and phi(S-W/S) (S-W substitutes S), respectively. The values of these constants depend on the physicochemical properties of the probe and the medium. We tested, for the first time, the applicability of a new solvation free energy relationship: phi = constant + a alpha(BM) + b beta(BM) + s(pi*(BM) + d delta) + p log P(BM), where a, b, s, and p are regression coefficients alpha(BM), beta(BM), and pi*(BM) are solvatochromic parameters of the BM, delta is a correction term for pi*, and log P is an empirical scale of lipophilicity. Correlations were carried out with two-, three-, and four-medium descriptors. In all cases, three descriptors gave satisfactory correlations; use of four parameters gave only a marginal increase of the goodness of fit. For phi(W/S), the most important descriptor was found to be the lipophilicity of the medium; for phi(S-W/W) and phi(S-W/S), solvent basicity is either statistically relevant or is the most important descriptor. These responses are different from those of E(T)(probe) of many solvatochromic indicators in pure solvents, where the importance of solvent basicity is usually marginal, and can be neglected.

Solvation in Pure Liquids: What Can Be Learned from the Use of Pairs of Indicators?

The solvation of six solvatochromic probes in a large number of solvents (33-68) was examined at 25 degrees C. The probes employed were the following: 2,6-diphenyl-4-(2,4,6-triphenylpyridinium-1-yl) phenolate (RB); 4-[(E)2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePM; 1-methylquinolinium-8-olate, QB; 2-bromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr, 2,6-dichloro-4-(2,4,6-triphenyl pyridinium-1-yl) phenolate (WB); and 2,6-dibromo-4-[(E)-2-(1-methylpyridinium-4-yl)ethenyl] phenolate, MePMBr(2), respectively. Of these, MePMBr is a novel compound. They can be grouped in three pairs, each with similar pK(a) in water but with different molecular properties, for example, lipophilicity and dipole moment. These pairs are formed by RB and MePM; QB and MePMBr; WB and MePMBr(2), respectively. Theoretical calculations were carried out in order to calculate their physicochemical properties including bond lengths, dihedral angles, dipole moments, and wavelength of absorption of the intramolecular charge-transfer band in four solvents, water, methanol, acetone, and DMSO, respectively. The data calculated were in excellent agreement with available experimental data, for example, bond length and dihedral angles. This gives credence to the use of the calculated properties in explaining the solvatochromic behaviors observed. The dependence of an empirical solvent polarity scale E(T)(probe) in kcal/mol on the physicochemical properties of the solvent (acidity, basicity, and dipolarity/polarizability) and those of the probes (pK(a), and dipole moment) was analyzed by using known multiparameter solvation equations. For each pair of probes, values of E(T)(probe) (for example, E(T)(MePM) versus E(T)(RB)) were found to be linearly correlated with correlation coefficients, r, between 0.9548 and 0.9860. For the mercyanine series, the values of E(T)(probe) also correlated linearly, with (r) of 0.9772 (MePMBr versus MePM) and 0.9919 (MePMBr(2) versus MePM). The response of each pair of probes (of similar pK(a)) to solvent acidity is the same, provided that solute-solvent hydrogen-bonding is not seriously affected by steric crowding (as in case of RB). We show, for the first time, that the response to solvent dipolarity/polarizability is linearly correlated to the dipole moment of the probes. The successive introduction of bromine atoms in MePM (to give MePMBr, then MePMBr(2)) leads to the following linear decrease: pK(a) in water, length of the phenolate oxygen-carbon bond, length of the central ethylenic bond, susceptibility to solvent acidity, and susceptibility to solvent dipolarity/polarizability. Thus studying the solvation of probes whose molecular structures are varied systematically produces a wealth of information on the effect of solute structure on its solvation. The results of solvation of the present probes were employed in order to test the goodness of fit of two independent sets of solvent solvatochromic parameters.

Swedish translation and psychometric testing of the safety attitudes questionnaire (operating room version)

Background: Tens of millions of patients worldwide suffer from avoidable disabling injuries and death every year. Measuring the safety climate in health care is an important step in improving patient safety. The most commonly used instrument to measure safety climate is the Safety Attitudes Questionnaire (SAQ). The aim of the present study was to establish the validity and reliability of the translated version of the SAQ. Methods: The SAQ was translated and adapted to the Swedish context. The survey was then carried out with 374 respondents in the operating room (OR) setting. Data was received from three hospitals, a total of 237 responses. Cronbach's alpha and confirmatory factor analysis (CFA) was used to evaluate the reliability and validity of the instrument. Results: The Cronbach's alpha values for each of the factors of the SAQ ranged between 0.59 and 0.83. The CFA and its goodness-of-fit indices (SRMR 0.055, RMSEA 0.043, CFI 0.98) showed good model fit. Intercorrelations between the factors safety climate, teamwork climate, job satisfaction, perceptions of management, and working conditions showed moderate to high correlation with each other. The factor stress recognition had no significant correlation with teamwork climate, perception of management, or job satisfaction. Conclusions: Therefore, the Swedish translation and psychometric testing of the SAQ (OR version) has good construct validity. However, the reliability analysis suggested that some of the items need further refinement to establish sound internal consistency. As suggested by previous research, the SAQ is potentially a useful tool for evaluating safety climate. However, further psychometric testing is required with larger samples to establish the psychometric properties of the instrument for use in Sweden.

Egg production curve fitting using nonlinear models for selected and nonselected lines of White Leghorn hens

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A quantitative nature of somatic embryogenesis in soybean

The objectives of this research were to investigate the genetic parameters associated with the in vitro formation of somatic embryos in soybean and to determine the effect of light intensity on the embryogenic capability of F-1, F-2, and backcross (RC1P1 and RC1P2) progenies derived from crosses between embryogenic (IAS-5 and Embrapa-1) and nonembryogenic (Parana) cultivars. Immature cotyledons (4-6 mm in length) derived from the parental lines, F-1, F-2, RC1P1, and RC1P2 were grown for 90 d on the inductive N10 medium, after which the number of somatic embryos was recorded. Chi-square tests for goodness of fit showed that the genetic component of the somatic embryogenesis trait is controlled in a quantitative manner by approximately 10 genes. A normal distribution for somatic embryo formation in the F-2 generations was observed reinforcing the quantitative nature of the trait. Variation in light intensity (8-12 and 27-33 mu mol m(-2) s(-1)) had no effect on somatic embryo formation in the parental material tested.

Models for the analysis of growth curves for rearing tinamous (Rhynchotus rufescens) in captivity

Growth curves models provide a visual assessment of growth as a function of time, and prediction body weight at a specific age. This study aimed at estimating tinamous growth curve using different models, and at verifying their goodness of fit. A total number 11,639 weight records from 411 birds, being 6,671 from females and 3,095 from males, was analyzed. The highest estimates of a parameter were obtained using Brody (BD), von Bertalanffy (VB), Gompertz (GP,) and Logistic function (LG). Adult females were 5.7% heavier than males. The highest estimates of b parameter were obtained in the LG, GP, BID, and VB models. The estimated k parameter values in decreasing order were obtained in LG, GP, VB, and BID models. The correlation between the parameters a and k showed heavier birds are less precocious than the lighter. The estimates of intercept, linear regression coefficient, quadratic regression coefficient, and differences between quadratic coefficient of functions and estimated ties of quadratic-quadratic-quadratic segmented polynomials (QQQSP) were: 31.1732 +/- 2.41339; 3.07898 +/- 0.13287; 0.02689 +/- 0.00152; -0.05566 +/- 0.00193; 0.02349 +/- 0.00107, and 57 and 145 days, respectively. The estimated predicted mean error values (PME) of VB, GP, BID, LG, and QQQSP models were, respectively, 0.8353; 0.01715; -0.6939; -2.2453; and -0.7544%. The coefficient of determination (RI) and least square error values (MS) showed similar results. In conclusion, the VB and the QQQSP models adequately described tinamous growth. The best model to describe tinamous growth was the Gompertz model, because it presented the highest R-2 values, easiness of convergence, lower PME, and the easiness of parameter biological interpretation.

Comparison of different nonlinear functions to describe Nelore cattle growth

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)