Sensitivity to initial conditions in the route-finder model.

A model of stimulus generalization [Staddon, J.E.R., Reid, A.K., 1990. On the dynamics of generalization. Psychol. Rev. 97, 576-578] was extended by Reid and Staddon [Reid, A.K., Staddon, J.E.R., 1998. A dynamic route finder for the cognitive map. Psychol. Rev. 105, 585-601] to account for the route-finder issue in the Tolman-Guthrie discussion about cognitive maps. This deterministic model has been described as sensitive to initial conditions in terms of the parameters of a diffusion equation [Reid, A.K., Staddon, J.E.R., 1998. A dynamic route finder for the cognitive map. Psychol. Rev. 105, 585-601]. A simulation study was carried out to test this assertion, evaluating whether the pattern of variation in the model output resembled a chaotic pattern. Results indicate that the model is sensitive to initial conditions, suggesting that the spatial navigation task addressed by this model involves non-linear relationships and complexity beyond the apparent simplicity of the stimulus generalization process.

Asthma pharmacogenetic study using finite mixture models to handle drug-response heterogeneity.

AIMS: Typically, only a proportion of the patients suffering from common diseases respond to frequently prescribed drugs. Since the presence of drug nonresponders in pharmacogenetic studies can adversely affect statistical power we propose a method to restrict genetic tests to drug responders only. In this paper, we estimate drug nonresponse in a clinical trial for the asthma drug montelukast as either the result of an inactive genetic variant or the presence of subgroups of patients not responding to the drug. MATERIALS & METHODS: We propose finite mixture models where unobserved (latent) categorical variables represent either a drug responder or nonresponder class. Analytical results show this method can substantially improve power by testing for genetic variants only in the drug-responder class. We also demonstrate how, if appropriate, placebo data can be used to further increase power to detect genetic effects. RESULTS: It was estimated that only 25-30% of the subjects responded to the drug montelukast. Genetic-association tests confined to the responder group resulted in a substantial increase in explained genetic variance, between 10.3 and 13.2%, for four markers in the arachidonate 5-lipoxigenase (ALOX5) and cysteinyl leukotriene receptor 1 (CYSLTR1) genes. CONCLUSION: The presence of subgroups of patients that do not respond to the drug was an important reason for nonresponse. Additional analyses using finite mixture models in pharmacogenetic studies may provide insight into drug nonresponse and a better discrimination between true and false discoveries.

In silico whole genome association scan for murine prepulse inhibition.

BACKGROUND: The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. METHODOLOGY/PRINCIPAL FINDINGS: We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. CONCLUSIONS/SIGNIFICANCE: These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.

Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast.

OBJECTIVE: Interindividual clinical response to leukotriene modifiers is highly variable, and less efficacious than inhaled corticosteroids in treating asthma. Genetic variability in 5-lipoxygenase biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers. METHODS: Using data from two clinical trials of 12-week duration, post-hoc analyses were performed in 174 patients randomized to montelukast. Associations between polymorphisms in 10 candidate genes (ALOX5, ALOX5AP, LTC4S, CYSLTR1, CYSLTR2, PLA2G4A, CYP2C9, CYP3A4, ADRB2, and NR3C1) and response to montelukast were modeled using change in morning peak expiratory flow and forced expiratory volume in 1 s (FEV1) to define the response phenotype. RESULTS: In our sample, eight out of 25 markers in 10 candidate genes were statistically associated with response to montelukast, with an estimated proportion of false discoveries of 16%. The strongest statistical evidence of clinically relevant pharmacogenetic effects peak expiratory flow were identified in CYSLTR2 (rs91227 and rs912278; P=0.02 and P=0.02, respectively) and ALOX5 (rs4987105 and rs4986832; P=0.01 and P=0.01, respectively). Patients with these variant genotypes, found in roughly 10-13% of patients, had an 18-25% improvement in peak expiratory flow. In contrast, the majority of patients with the wild-type alleles had only a marginal (8-10%) improvement. CONCLUSIONS: The overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.

Adquisición de aa respuesta de congelamiento deratas: diferencias sexuales en adolescentes y adultos / Acquisitio of frreezing response in rats: sex differences in adolescents and adults

El Condicionamiento Pavloviano de Miedo es uno de los modelos preclínicos más comunes en el estudio del Trastorno de Estrés Post-traumático. El objetivo de la presente investigación consistió en utilizarlo como biomodelo para el estudio de las diferencias sexuales que caracterizan este síndrome, así como elaborar una descripción preliminar de las diferencias a lo largo de la trayectoria ontogenética. Se utilizaron 45 sujetos, de tres camadas diferentes de ratas ingenuas de ascendencia Wistar, 18 machos y 27 hembras, dos aproximadamente por camada para cada uno de los dos grupos experimentales: animales adolescentes y adultos. Los resultados señalan diferencias significativas en la segunda medición del estímulo condicionado en la interacción entre sexo y edad y al comparar las tres mediciones del estímulo condicionado. Se discuten los resultados en torno a las discrepancias en la literatura respecto al efecto de las variables evaluadas en la adquisición de miedo condicionado.

Pavlovian fear conditioning is one of the most popular preclinical models in the study of Post-Traumatic Stress Disorder (PTSD). The aim of the present research was explore the sex differences that characterize PTSD by means of this experimental paradigm, as well as to offer a preliminary description of how these sex differences behave throughout development. Forty five native rats, of Wistar descent were used as subjects, with 18 males and 27 females approximately balanced by litter across the two experimental groups: adolescents and adults. The results show significant differences in the second measurement of the conditioned stimulus in the interaction between sex and age and to compare the tree measurements of the conditioned stimulus. Results are discussed regarding the discrepancies in the literature regarding the effect of the variables evaluated in the acquisition of Conditioned fear.

A method for analyzing strain differences in acquisition of IV cocaine self-administration in mice.

The techniques currently available for studying drug self-administration in animals offer the unique opportunity to carry out micro-analysis of initial episodes of drug use which are extremely difficult to obtain for human subjects. Nonetheless, traditional self-administration techniques do not allow a cost-effective output of large sample sizes needed for genetic analysis. Additionally, the statistical techniques that allow the integration of within-subject temporal data with genetic information are scant. We therefore propose a two-stage method for analyzing strain differences in dynamic phenotypes for a high-throughput version of the self-administration procedure. On a first phenotype-refinement stage, a change-point algorithm (Gallistel et al. (2004) Proc. Natl Acad. Sci. USA 101:13124-13131) was used to separate individual drug self-administration response curves into three distinct components. In a second stage, strains differences in these indexes were assessed. This two-stage approach is illustrated with drug self-administration data and through a computer simulation.

Análisis intra: sesión de la extinción del condicionamiento pavloviano de miedo usando regresión robusta / . Within-session analysis of the extinction of pavlovian fear-conditioning using robust regression

El análisis de datos de extinción en experimentos de miedo condicionado ha involucrado, tradicionalmente, el uso de modelos lineales estándar, primordialmente ANOVA de diferencias entre grupos de sujetos sometidos a diferentes protocolos de extinción, manipulaciones farmacológicas o algún otro tratamiento. Aún cuando algunos estudios reportan diferencias individuales en indicadores como tasas de supresión o porcentajes de congelamiento, esas diferencias no son incluidas en el análisis estadístico. Los patrones de respuesta intra-sujeto son entonces promediados usando ventanas temporales de baja resolución, las cuales pueden ignorar esta dinámica del desempeño individual. Este trabajo ilustra un procedimiento analítico alternativo que consta de 2 pasos: estimación de la tendencia para los datos intra-sesión y el análisis de las diferencias entre-grupo usando la tendencia como variable de respuesta. Este procedimiento se pone a prueba usando datos reales de extinción de miedo condicionado, comparando estimaciones de tendencia robusta vía Mínimos Cuadrados Medianos con Mínimos Cuadrados Ordinarios, y comparando las diferencias de grupo usando la pendiente robusta versus la mediana del porcentaje de congelamiento como variable dependiente.

Traditionally , the analysis of extinction data in fear conditioning experimentshas involved the use of standard linear models, mostly ANOVA of between-group differences of subjects that have undergone different extinction protocols, pharmacological manipulations or some other treatment. Although some studies reportindividual differences in quantities such as suppression rates or freezing percentages, these differences are not included in the statistical modeling. Withinsubject response patterns are then averaged using coarse-grain time windows which can overlook these individual performance dynamics. Here we illustrate an alternative analytical procedure consisting of 2 steps: the estimation of a trend for within-session data and analysis of group differences in trend as main outcome. This procedure is tested on real fear-conditioning extinction data, comparing trend estimates via Ordinary Least Squares (OLS) and robust Least Median of Squares (LMS) regression estimates, as well as comparing between-group differences and analyzing mean freezing percentage versus LMS slopes as outcomes.

Effect of sampling frequency on automatically-generated activity and freezing scores in a Pavlovian fear-conditioning preparation / Efecto de la frecuencia de muestreo sobre los índices automáticos de actividad y congelamiento en un procedimiento de condicionamiento pavloviano del miedo

Conditioned freezing has long held conceptual importance in behavior analysis, being pivotal in the explanation of anxiety-like behavior. Although initially measured indirectly, through its disruptive effect on operant behavior (conditioned suppression), and later by direct observation, automated techniques of measuring movement have recently become available, which also enable theme asurement of conditioned freezing. These video processing techniques allow for the direct and virtually continuous measurement of activity, as compared to the traditional interval sampling approach of direct observation. We examined whether automatically generated freezing and movement scores were equally sensitive to traditional Pavlovian conditioning manipulations, and how this sensitivity was affected by the sampling frequency of the data. Extinction data for 42 mice were collected at a rate of 30 Hz, transformed via re-sampling and analyzed by a generalized linear model to determine the effect size for the presence of the conditioned stimulus for each individual time series under four conditions: high and low resolution raw activity scores and high and low resolution dichotomous freezing scores. The resolution of the data proved to be the most important dimension in estimating local changes in the level of the individual time-series, with activity and freezings cores presenting comparable effect sizes. In contrast with the above, only high-resolution activity measurements proved to be effective in detecting local changes in trends.

La respuesta condicionada de congelamiento tiene importancia conceptual de larga data para el Análisis Conductual, siendo clave en la explicación de las conductasde ansiedad. Aún cuando inicialmente fue medida deforma indirecta, mediante sus efectos sobre la conducta operante (como en el arreglo de supresión condicionada) y más tarde mediante la observación directa, recientemente se han hecho disponibles alternativas para la medición automática del movimiento que permiten también la medición del congelamiento condicionado. Estas nuevas técnicas de video permiten la medición directa y virtualmente constante de la actividad del organismo, por contraposición a las técnicas tradicionales de muestreo de tiempo características del registro observacional. En el presente artículo se compara el efecto de manipulaciones pavlovianas tradicionales sobre la sensibilidad de los delos índices automatizados de congelamiento y actividad, así como el posible efecto de la densidad de muestreo sobre dicha sensibilidad. Para ello se analizan datos provenientes de sesiones de extinción pavloviana de 42 ratones, recogidos con una frecuencia 30 Hz y transformados mediante una técnica de remuestreo, para luego ser analizado mediante un modelo lineal generalizado, a fin de determinar la magnitud del efecto de la presencia del estímulo condicionado en cada una de cuatro condiciones: puntajes brutos de actividad de alta y baja resolución y puntajes dicotómicos de congelamiento de alta y baja resolución. La resolución de los datos mostró ser la dimensión más relevante para la estimación de cambios locales de nivel en las series temporales individuales, siendo dichos cambios igualmente fáciles de detectar en los índices de congelamiento y de actividad. A diferencia de lo anterior, sólo las medidas de actividad de alta resolución permitieron la detección de cambios locales de tendencia.

Análisis cuantitativo de la dinámica individual de trabajos de grado de Psicología / Quantitative analysis of the individual dynamics of Psychology theses

El presente trabajo analiza longitudinalmente tres cohortes de trabajos (n = 57) realizados por estudiantes de último año de pregrado en psicología, de la Universidad Católica Andrés Bello, usando cinco medidas de progreso. Se prueba un modelo aditivo generalizado para predecir el tiempo de culminación de los trabajos de grado, medido en dos niveles: temprano y demorado. Las medidas de magnitud de efecto favorecen un modelo de indicadores en múltiples dimensiones, por encima de uno de progreso global. La trayectoria de los indicadores a lo largo de las cinco medidas facilita diferenciar la culminación temprana de la demorada. Las probabilidades de culminación estimadas a partir del modelo basado en dimensiones permiten establecer niveles de oscilación diferenciales para los distintos tiempos de culminación. Los indicadores de progreso inicial habilitan predecir la culminación temprana con un 71% de acierto, mientras que la medición final tiene un acierto de 89%. Los resultados apoyan la efectividad del sistema de supervisión y el análisis de la dinámica de la progresión de los trabajos de grado desde un modelo de demora de tarea, centrado en la relación entre el monto de tarea completada y las metas temporales.

Three cohorts of undergraduate psychology theses (n = 57) performed by last year undergraduate psychology students from Universidad Católica Andrés Bello, were monitored using 5 longitudinal measurements of progression. A Generalized Additive Model, to predict the completion time of the theses, is tested against two completion times: early and delayed. Effect size measures favor a multiple dimension model over a global progress model. The trajectory of the indicators through the 5 measurements allows the differentiation between early and delayed completion. The completion probabilities estimated by the dimensional model allow the identification of differential oscillation levels for the distinct completion times. The initial progression indicators allow the prediction of early completion with a 71% success rate, while the final measurement shows a success rate of 89%. The results support the effectiveness of the supervisory system and the analysis of the progression dynamics of the theses from a task-delay model, focused on the relationship between the amount oftask completion and the deadlines.