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Constraints arise naturally in many scientific experiments/studies such as in, epidemiology, biology, toxicology, etc. and often researchers ignore such information when analyzing their data and use standard methods such as the analysis of variance (ANOVA). Such methods may not only result in a loss of power and efficiency in costs of experimentation but also may result poor interpretation of the data. In this paper we discuss constrained statistical inference in the context of linear mixed effects models that arise naturally in many applications, such as in repeated measurements designs, familial studies and others. We introduce a novel methodology that is broadly applicable for a variety of constraints on the parameters. Since in many applications sample sizes are small and/or the data are not necessarily normally distributed and furthermore error variances need not be homoscedastic (i.e. heterogeneity in the data) we use an empirical best linear unbiased predictor (EBLUP) type residual based bootstrap methodology for deriving critical values of the proposed test. Our simulation studies suggest that the proposed procedure maintains the desired nominal Type I error while competing well with other tests in terms of power. We illustrate the proposed methodology by re-analyzing a clinical trial data on blood mercury level. The methodology introduced in this paper can be easily extended to other settings such as nonlinear and generalized regression models. [ABSTRACT FROM AUTHOR]

As a performance measure for a prediction model, the area under the receiver operating characteristic curve (AUC) is insensitive to the addition of strong markers. A number of measures sensitive to performance change have recently been proposed; however, these relative-performance measures may lead to self-contradictory conclusions. This paper examines alternative performance measures for prediction models: the Lorenz curve-based Gini and Pietra indices, and a standardized version of the Brier score, the scaled Brier. Computer simulations are performed in order to study the sensitivity of these measures to performance change when a new marker is added to a baseline model. When the discrimination power of the added marker is concentrated in the gray zone of the baseline model, the AUC and the Gini show minimal performance improvements. The Pietra and the scaled Brier show more significant improvements in the same situation, comparatively. The Pietra and the scaled Brier indices are therefore recommended for prediction model performance measurement, in light of their ease of interpretation, clinical relevance and sensitivity to gray-zone resolving markers. [ABSTRACT FROM AUTHOR]

Knowledge of how a population of cancerous cells progress through the cell cycle is vital if the population is to be treated effectively, as treatment outcome is dependent on the phase distributions of the population. Estimates on the phase distribution may be obtained experimentally however the errors present in these estimates may effect treatment efficacy and planning. If mathematical models are to be used to make accurate, quantitative predictions concerning treatments, whose efficacy is phase dependent, knowledge of the phase distribution is crucial. In this paper it is shown that two different transition rates at the - checkpoint provide a good fit to a growth curve obtained experimentally. However, the different transition functions predict a different phase distribution for the population, but both lying within the bounds of experimental error. Since treatment outcome is effected by the phase distribution of the population this difference may be critical in treatment planning. Using an age-structured population balance approach the cell cycle is modelled with particular emphasis on the - checkpoint. By considering the probability of cells transitioning at the - checkpoint, different transition functions are obtained. A suitable finite difference scheme for the numerical simulation of the model is derived and shown to be stable. The model is then fitted using the different probability transition functions to experimental data and the effects of the different probability transition functions on the model's results are discussed. [ABSTRACT FROM AUTHOR]

In genetic association studies, tests for Hardy-Weinberg proportions are often employed as a quality control checking procedure. Missing genotypes are typically discarded prior to testing. In this paper we show that inference for Hardy-Weinberg proportions can be biased when missing values are discarded. We propose to use multiple imputation of missing values in order to improve inference for Hardy-Weinberg proportions. For imputation we employ a multinomial logit model that uses information from allele intensities and/or neighbouring markers. Analysis of an empirical data set of single nucleotide polymorphisms possibly related to colon cancer reveals that missing genotypes are not missing completely at random. Deviation from Hardy-Weinberg proportions is mostly due to a lack of heterozygotes. Inbreeding coefficients estimated by multiple imputation of the missings are typically lowered with respect to inbreeding coefficients estimated by discarding the missings. Accounting for missings by multiple imputation qualitatively changed the results of 10 to 17% of the statistical tests performed. Estimates of inbreeding coefficients obtained by multiple imputation showed high correlation with estimates obtained by single imputation using an external reference panel. Our conclusion is that imputation of missing data leads to improved statistical inference for Hardy-Weinberg proportions. [ABSTRACT FROM AUTHOR]

Designs of the double sampling (DS) chart are traditionally based on the average run length (ARL) criterion. However, the shape of the run length distribution changes with the process mean shifts, ranging from highly skewed when the process is in-control to almost symmetric when the mean shift is large. Therefore, we show that the ARL is a complicated performance measure and that the median run length (MRL) is a more meaningful measure to depend on. This is because the MRL provides an intuitive and a fair representation of the central tendency, especially for the rightly skewed run length distribution. Since the DS chart can effectively reduce the sample size without reducing the statistical efficiency, this paper proposes two optimal designs of the MRL-based DS chart, for minimizing (i) the in-control average sample size (ASS) and (ii) both the in-control and out-of-control ASSs. Comparisons with the optimal MRL-based EWMA and Shewhart charts demonstrate the superiority of the proposed optimal MRL-based DS chart, as the latter requires a smaller sample size on the average while maintaining the same detection speed as the two former charts. An example involving the added potassium sorbate in a yoghurt manufacturing process is used to illustrate the effectiveness of the proposed MRL-based DS chart in reducing the sample size needed. [ABSTRACT FROM AUTHOR]

: Regression analysis with a bounded outcome is a common problem in applied statistics. Typical examples include regression models for percentage outcomes and the analysis of ratings that are measured on a bounded scale. In this paper, we consider beta regression, which is a generalization of logit models to situations where the response is continuous on the interval (0,1). Consequently, beta regression is a convenient tool for analyzing percentage responses. The classical approach to fit a beta regression model is to use maximum likelihood estimation with subsequent AIC-based variable selection. As an alternative to this established - yet unstable - approach, we propose a new estimation technique called boosted beta regression. With boosted beta regression estimation and variable selection can be carried out simultaneously in a highly efficient way. Additionally, both the mean and the variance of a percentage response can be modeled using flexible nonlinear covariate effects. As a consequence, the new method accounts for common problems such as overdispersion and non-binomial variance structures. [ABSTRACT FROM AUTHOR]

Current metrics for estimating a scientist’s academic performance treat the author’s publications as if these were solely attributable to the author. However, this approach ignores the substantive contributions of co-authors, leading to misjudgments about the individual’s own scientific merits and consequently to misallocation of funding resources and academic positions. This problem is becoming the more urgent in the biomedical field where the number of collaborations is growing rapidly, making it increasingly harder to support the best scientists. Therefore, here we introduce a simple harmonic weighing algorithm for correcting citations and citation-based metrics such as the h-index for co-authorships. This weighing algorithm can account for both the nvumber of co-authors and the sequence of authors on a paper. We then derive a measure called the ‘profit (p)-index’, which estimates the contribution of co-authors to the work of a given author. By using samples of researchers from a renowned Dutch University hospital, Spinoza Prize laureates (the most prestigious Dutch science award), and Nobel Prize laureates in Physiology or Medicine, we show that the contribution of co-authors to the work of a particular author is generally substantial (i.e., about 80%) and that researchers’ relative rankings change materially when adjusted for the contributions of co-authors. Interestingly, although the top University hospital researchers had the highest h-indices, this appeared to be due to their significantly higher p-indices. Importantly, the ranking completely reversed when using the profit adjusted h-indices, with the Nobel laureates having the highest, the Spinoza Prize laureates having an intermediate, and the top University hospital researchers having the lowest profit adjusted h-indices, respectively, suggesting that exceptional researchers are characterized by a relatively high degree of scientific independency/originality. The concepts and methods introduced here may thus provide a more fair impression of a scientist’s autonomous academic performance. [ABSTRACT FROM AUTHOR]

To facilitate analysis and understanding of biological systems, large-scale data are often integrated into models using a variety of mathematical and computational approaches. Such models describe the dynamics of the biological system and can be used to study the changes in the state of the system over time. For many model classes, such as discrete or continuous dynamical systems, there exist appropriate frameworks and tools for analyzing system dynamics. However, the heterogeneous information that encodes and bridges molecular and cellular dynamics, inherent to fine-grained molecular simulation models, presents significant challenges to the study of system dynamics. In this paper, we present an algorithmic information theory based approach for the analysis and interpretation of the dynamics of such executable models of biological systems. We apply a normalized compression distance (NCD) analysis to the state representations of a model that simulates the immune decision making and immune cell behavior. We show that this analysis successfully captures the essential information in the dynamics of the system, which results from a variety of events including proliferation, differentiation, or perturbations such as gene knock-outs. We demonstrate that this approach can be used for the analysis of executable models, regardless of the modeling framework, and for making experimentally quantifiable predictions. [ABSTRACT FROM AUTHOR]