Impact of selection bias on the evaluation of clusters of chemical compounds in the drug discovery process

Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess the potential of each cluster, and with appropriate statistical methods, these qualitative assessments can be quantified into a success probability for each of them. However, one crucial element often overlooked is the procedure by which the clusters are assigned to/selected by the experts for evaluation. In the present work, the impact such a procedure may have on the statistical analysis and the entire evaluation process is studied. It has been shown that some implementations of the selection procedure may seriously compromise the validity of the evaluation even when the rating and selection processes are independent. Consequently, the fully random allocation of the clusters to the experts is strongly advocated. Copyright © 2014 John Wiley & Sons, Ltd.     

Teacher ethnicity,student ethnicity,and student outcomes

A review of the empirical literature was conducted to establish the relation between teacher and student ethnicity, and cognitive and noncognitive student outcomes. It was hypothesized that ethnic teacher–student congruence results in more favorable outcomes for especially minority students. A total of 24 quantitative studies focusing on primary and secondary education in the United States were reviewed. The results show that there is as yet little unambiguous empirical evidence that a stronger degree of ethnic match be it in the form of a one-to-one coupling of a teacher to students with the same ethnic background, or a larger share of ethnic minority teachers at an ethnically mixed school, leads to predominantly positive results. Insofar positive effects were found, they apply to a greater extent to subjective teacher evaluations than to objective achievement outcome measures.     

Cancer Dose-Response Modeling of Epidemiological Data on Worker Exposures to Aldrin and Dieldrin

The paper applies classical statistical principles to yield new tools for risk assessment and makes new use of epidemiological data for human risk assessment. An extensive clinical and epidemiological study of workers engaged in the manufacturing and formulation of aldrin and dieldrin provides occupational hygiene and biological monitoring data on individual exposures over the years of employment and provides unusually accurate measures of individual lifetime average daily doses. In the cancer dose-response modeling, each worker is treated as a separate experimental unit with his own unique dose. Maximum likelihood estimates of added cancer risk are calculated for multistage, multistage-Weibull, and proportional hazards models. Distributional characterizations of added cancer risk are based on bootstrap and relative likelihood techniques. The cancer mortality data on these male workers suggest that low-dose exposures to aldrin and dieldrin do not significantly increase human cancer risk and may even decrease the human hazard rate for all types of cancer combined at low doses (e.g., 1 g/kg/day). The apparent hormetic effect in the best fitting dose-response models for this data set is statistically significant. The decrease in cancer risk at low doses of aldrin and dieldrin is in sharp contrast to the U.S. Environmental Protection Agency's upper bound on cancer potency based on mouse liver tumors. The EPA's upper bound implies that lifetime average daily doses of 0.0000625 and 0.00625 g/kg body weight/day would correspond to increased cancer risks of 0.000001 and 0.0001, respectively. However, the best estimate from the Pernis epidemiological data is that there is no increase in cancer risk in these workers at these doses or even at doses as large as 2 g/kg/day.     

An information-theoretic approach to surrogate-marker evaluation with failure time endpoints

Over the last decades, the evaluation of potential surrogate endpoints in clinical trials has steadily been growing in importance, not only thanks to the availability of ever more potential markers and surrogate endpoints, also because more methodological development has become available. While early work has been devoted, to a large extent, to Gaussian, binary, and longitudinal endpoints, the case of time-to-event endpoints is in need of careful scrutiny as well, owing to the strong presence of such endpoints in oncology and beyond. While work had been done in the past, it was often cumbersome to use such tools in practice, because of the need for fitting copula or frailty models that were further embedded in a hierarchical or two-stage modeling approach. In this paper, we present a methodologically elegant and easy-to-use approach based on information theory. We resolve essential issues, including the quantification of “surrogacy” based on such an approach. Our results are put to the test in a simulation study and are applied to data from clinical trials in oncology. The methodology has been implemented in R.     

A sensitivity analysis of probabilistic sensitivity analysis in terms of the density function for the input variables

Probabilistic sensitivity analysis (SA) allows to incorporate background knowledge on the considered input variables more easily than many other existing SA techniques. Incorporation of such knowledge is performed by constructing a joint density function over the input domain. However, it rarely happens that available knowledge directly and uniquely translates into such a density function. A naturally arising question is then to what extent the choice of density function determines the values of the considered sensitivity measures. In this paper we perform simulation studies to address this question. Our empirical analysis suggests some guidelines, but also cautions to practitioners in the field of probabilistic SA.     

A family of measures to evaluate scale reliability in a longitudinal setting

Summary.  The concept of reliability denotes one of the most important psychometric properties of a measurement scale. Reliability refers to the capacity of the scale to discriminate between subjects in a given population. In classical test theory, it is often estimated by using the intraclass correlation coefficient based on two replicate measurements. However, the modelling framework that is used in this theory is often too narrow when applied in practical situations. Generalizability theory has extended reliability theory to a much broader framework but is confronted with some limitations when applied in a longitudinal setting. We explore how the definition of reliability can be generalized to a setting where subjects are measured repeatedly over time. On the basis of four defining properties for the concept of reliability, we propose a family of reliability measures which circumscribes the area in which reliability measures should be sought. It is shown how different members assess different aspects of the problem and that the reliability of the instrument can depend on the way that it is used. The methodology is motivated by and illustrated on data from a clinical study on schizophrenia. On the basis of this study, we estimate and compare the reliabilities of two different rating scales to evaluate the severity of the disorder.     

Emancipation and Self-determination of People with Learning Disabilities and Down-sizing Institutional Care

In Arduin, an organisation for services to people with learning disabilities in the Netherlands, the emancipation and self-determination of people with learning disabilities has been positively adopted as fundamental in order to secure the best possible quality of life of the clients. The client is being encouraged in several ways in a development from a position of dependence towards self-determination. The services provided by the organisation had to be adjusted accordingly and are also going through a transition from 'providing a total care service' towards 'offering the support that the client desires'. In this article the background and developments in perception are being outlined, and those dimensions in quality of life are elaborated that are seen as most essential in the innovation: inclusion, self-determination and personal development. The choices that were made as a consequence in Arduin and most fundamental the choice to dismantle the institution are described.     

The role of crisis in family crisis intervention: Do crisis experience and crisis change matter?

Evaluation studies of crisis intervention have focused on prevention of out-of-home placement of children or family functioning, but largely neglected the aspect of crisis. The present study examined crisis in 183 families receiving Family Crisis Intervention (FCI), addressing crisis characteristics and crisis change. In questionnaires children and parents were asked about their definition and experience of crisis and about their need for help. Results show that all families but one were in crisis at the beginning of the intervention, although the perception and extent of crisis differed among respondents. Crisis decreased from baseline to posttest according to clients and crisis intervention workers, but was not absent after the intervention. Combined with an unexpected pattern of reported family balance in the months before FCI, this result challenges the 4-6 weeks time span assumption of a crisis period. Variations in perception of crisis, clients' need for help, and possible crisis patterns are discussed, addressing theoretical and practical implications for family crisis intervention.     

Validation of a longitudinally measured surrogate marker for a time-to-event endpoint

The objective of this paper is to extend the surrogate endpoint validation methodology proposed by Buyse et al. (2000) to the case of a longitudinally measured surrogate marker when the endpoint of interest is time to some key clinical event. A joint model for longitudinal and event time data is required. To this end, the model formulation of Henderson et al. (2000) is adopted. The methodology is applied to a set of two randomized clinical trials in advanced prostate cancer to evaluate the usefulness of prostate-specific antigen (PSA) level as a surrogate for survival.