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.     

Asymptotic Variance of Semiparametric Estimators With Generated Regressors

We study the asymptotic distribution of three‐step estimators of a finite‐dimensional parameter vector where the second step consists of one or more nonparametric regressions on a regressor that is estimated in the first step. The first‐step estimator is either parametric or nonparametric. Using Newey's (1994) path‐derivative method, we derive the contribution of the first‐step estimator to the influence function. In this derivation, it is important to account for the dual role that the first‐step estimator plays in the second‐step nonparametric regression, that is, that of conditioning variable and that of argument.     

The impact of respondents and interviewers on interview speed in face-to-face interviews

In surveys carried out by interviewers trained according to the key principle of standardized interviewing it is assumed that the interviewer has only limited impact on the time a respondent needs to answer questions. In the paper the effects of interviewers and respondent characteristics on interview speed are analyzed simultaneously by means of a three-level random coefficient model. Data from the fifth round of the European Social Survey (ESS) are used. In twelve participating countries (CAPI) timers were implemented at several places in the questionnaire. Based on this time information the interview speed (number of questions asked per minute) was measured for each respondent during five modules of the questionnaire. The results support most of the expectations concerning the effects of the respondent characteristics. However, the results also indicate that, for all countries, interviewers strongly determine the interview speed and that interview length is not a simple linear function of the number of questions in a questionnaire.     

Visiting borders in education: A creative approach with children in primary education

This study engages with children sharing experiences of belonging at school, of receiving access and of exploring complex relationalities along shifting borders in educational spaces. Their understandings offer a magnifying glass on normativity, difference and social positions in school spaces. Through ‘flattening and folding’ with material and theoretical concepts, the authors map how qualitative data images made by children and theory constitute one another to make sense of complex relationalities discussed by children. The project desires to make sense of blurry borders that exclude children in educational contexts and to push borders in methods and ethics in research with children.