Research Interests: Statistics, Spatial Memory, Experience Design, Swimming, Learning and Memory, and 14 moreFemale, Animals, Male, Reaction Time, Spatial Learning, Behavioral Animal Models, Spatial Behavior, Longitudinal Studies, Rats, Longitudinal data, Pharmaceutical Statistics, Maze Learning, Right-censoring, and Morris water maze
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This paper deals with the analysis of data from a HET-CAM(VT) experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time-to-event like data, which are at the same time interval... more
This paper deals with the analysis of data from a HET-CAM(VT) experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time-to-event like data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data. Copyright © 2015 John Wiley & Sons, Ltd.
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In this paper, we propose an extension of this method for the case where several longitudinal profiles are recorded for the same individual. When dealing with more than one longitudinal variable, we have to take the correlation between... more
In this paper, we propose an extension of this method for the case where several longitudinal profiles are recorded for the same individual. When dealing with more than one longitudinal variable, we have to take the correlation between these variables into account in our classifi- cation. A full multivariate model would be the natural choice, but given the complexity of
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We consider a Plackett-Dale model to study familial transmittance of longevity. We focus the analysis on associations between mother, father and first child, and therefore we work with family clusters of equal size. We propose a series of... more
We consider a Plackett-Dale model to study familial transmittance of longevity. We focus the analysis on associations between mother, father and first child, and therefore we work with family clusters of equal size. We propose a series of tests to perform inferences on the model parameters. The methodology is applied to a demographic database of a Flemish village (18th-20th century).
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It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure... more
It is widely accepted that more needs to be done to bring new, safe, and efficacious drugs to the market. Cardiovascular toxicity detected both in early drug discovery as well as in the clinic, is a major contributor to the high failure rate of new molecules. The growth of translational safety offers a promising approach to improve the probability of success for new molecules. Here we describe a cross-company initiative to determine the concordance between the conscious telemetered dog and phase I outcome for 3 cardiovascular parameters. The data indicate that, in the context of the methods applied in this analysis, the ability to detect compounds that affect the corrected QT interval (QTc) was good within the 10-30x exposure range but the predictive or detective value for heart rate and diastolic blood pressure was poor. These findings may highlight opportunities to refine both the animal and the clinical study designs, as well as refocusing the assessment of value of dog cardiovas...
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Research Interests: Statistics, Population Genetics, Adoption, Survival Analysis, Multivariate Analysis, and 10 moreHumans, Case Study, Hiv Infection, Public health systems and services research, Combination drug therapy, Survival Time, Likelihood Functions, Overall Survival, Antiviral Agents, and Acquired immunodeficiency syndrome
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A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs pointed to... more
A statistical definition of surrogate endpoints as well as validation criteria was first presented by Prentice. Freedman et al. supplemented these criteria with the so-called proportion explained. Buyse and Molenberghs pointed to inadequacies of these criteria and suggested a new definition of surrogacy based on (i) the relative effect linking the overall effect of treatment on both endpoints and (ii) an individual-level measure of agreement between both endpoints. Using data from a randomized trial, they showed how a potential surrogate endpoint can be studied using a joint model for the surrogate and the true endpoint. Whereas Buyse and Molenberghs restricted themselves to the fairly simple cases of jointly normal and jointly binary outcomes, we treat the situation where the surrogate is binary and the true endpoint is continuous, or vice versa. In addition, we consider the case of ordinal endpoints. Further, Buyse et al. extended the approach of Buyse and Molenberghs to a meta-analytic context. We will adopt a similar approach for responses of a mixed data type.
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ABSTRACT
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Research Interests: Statistics, Spatial Memory, Experience Design, Swimming, Learning and Memory, and 14 moreFemale, Animals, Male, Reaction Time, Spatial Learning, Behavioral Animal Models, Spatial Behavior, Longitudinal Studies, Rats, Longitudinal data, Pharmaceutical Statistics, Maze Learning, Right-censoring, and Morris water maze
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Regarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements. As a step towards translation of preclinical... more
Regarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements. As a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dt(max) (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dt(max)/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil. Both techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dt(max) of 1000 mmHg/s (in the range of 2500 to 7500 mmHg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dt(max)/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%. The correlation found in this study could potentially enable a better--translational--assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.
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Measurements of both continuous and discrete outcomes are encountered in many statistical problems. Here we consider the particular context of teratology studies, where quantitative risk asessment is aimed at determining the effect of... more
Measurements of both continuous and discrete outcomes are encountered in many statistical problems. Here we consider the particular context of teratology studies, where quantitative risk asessment is aimed at determining the effect of dose on the probability that an individual fetus is malformed or of low birth weight, both being important measures of teratogenicity. We will introduce two different joint
Research Interests: Risk assessment, Biological Sciences, Environmental Sciences, Latent variable, Low Birth Weight, and 9 moreMathematical Sciences, Clustered Data, Quantitative risk assessment, Model Generation, Risk Assessment, Multivariate Normal Distribution, Generalized estimating equation, Developmental toxicity, and Probit Model
... The exposure metrics in these models are the cumulative heat exposure, dik × tik, which will be denoted by cik, and the effect of ... this model here (see Section 5). In addition, we fitted the data described in Section 2 using... more
... The exposure metrics in these models are the cumulative heat exposure, dik × tik, which will be denoted by cik, and the effect of ... this model here (see Section 5). In addition, we fitted the data described in Section 2 using generalized estimating equations (GEE), which are a ...