Setting the control limit at release for stability assurance.

A common task in quality control is to determine a control limit for a product at the time of release that incorporates its risk of degradation over time. Such a limit for a given quality measurement will be based on empirical stability data, the intended shelf life of the product and the stability specification. The task is particularly important when the registered specifications for release and stability are equal. We discuss two relevant formulations and their implementations in both a frequentist and Bayesian framework. The first ensures that the risk of a batch failing the specification is comparable at release and at the end of shelf life. The second is to screen out batches at release time that are at high risk of failing the stability specification at the end of their shelf life. Although the second formulation seems more natural from a quality assurance perspective, it usually renders a control limit that is too stringent. In this paper we provide theoretical insight in this phenomenon, and introduce a heat-map visualisation that may help practitioners to assess the feasibility of implementing a limit under the second formulation. We also suggest a solution when infeasible. In addition, the current industrial benchmark is reviewed and contrasted to the two formulations. Computational algorithms for both formulations are laid out in detail, and illustrated on a dataset.

Unbiased estimation of Langevin dynamics from time series with application to hippocampal field potentials in vitro.

The last decade showed an increased interest in Langevin equations for modeling time series recorded from complex dynamical systems. These equations allow to discriminate between deterministic (drift) and stochastic (diffusion) components of the recorded time series. In practice, the estimation of drift and diffusion is often based on approximations of the models' dynamics that are valid only for high sampling frequencies. Also, model assessment is not or only indirectly performed, potentially leading to false claims. In this study we compare the performance of an asymptotically unbiased estimation method with a generally used approximate method, demonstrating the necessity of using (asymptotically) unbiased estimators. Furthermore, we describe how confidence intervals for the unknown parameters can be constructed and how model assessment can be carried out. We apply the methodology to local field potentials recorded in vitro from mouse hippocampus from eight genetically different strains. The recorded field potentials turn out to be well described by linearly damped Langevin equations with parabolic diffusion. The modeling enables a dynamical interpretation of the spectral power of the field potentials. It reveals that observed spectral power differences in the field potentials across hippocampal regions are associated with differences in the deterministic component of the system, and it reveals transiently active current dipoles, which are not detectable by conventional methods. Also, all estimated parameters have significant heritabilities, which suggests that the Langevin equations capture biological relevant aspects of electrical hippocampal activity.

MicroRNAs in addiction: adaptation's middlemen?

A central question in addiction is how drug-induced changes in synaptic signaling are converted into long-term neuroadaptations. Emerging evidence reveals that microRNAs (miRNAs) have a distinct role in this process through rapid response to cellular signals and dynamic regulation of local mRNA transcripts. Because each miRNA can target hundreds of mRNAs, relative changes in the expression of miRNAs can greatly impact cellular responsiveness, synaptic plasticity and transcriptional events. These diverse consequences of miRNA action occur through coordination with genes implicated in addictions, the most compelling of these being the neurotrophin BDNF, the transcription factor cAMP-responsive element-binding protein (CREB) and the DNA-binding methyl CpG binding protein 2 (MeCP2). In this study, we review the recent progress in the understanding of miRNAs in general mechanisms of plasticity and neuroadaptation and then focus on specific examples of miRNA regulation in the context of addiction. We conclude that miRNA-mediated gene regulation is a conserved means of converting environmental signals into neuronal response, which holds significant implications for addiction and other psychiatric illnesses.

Dynamics underlying spontaneous human alpha oscillations: a data-driven approach.

Although the cognitive and clinical correlates of spontaneous human alpha oscillations as recorded with electroencephalography (EEG) or magnetoencephalography (MEG) are well documented, the dynamics underlying these oscillations is still a matter of debate. This study proposes a data-driven method to reveal the dynamics of these oscillations. It demonstrates that spontaneous human alpha oscillations as recorded with MEG can be viewed as noise-perturbed damped harmonic oscillations. This provides evidence for the hypothesis that these oscillations reflect filtered noise and hence do not possess limit-cycle dynamics. To illustrate the use of the model, we apply it to two data-sets in which a decrease in alpha power can be observed across conditions. The associated differences in the estimated model parameters show that observed decreases in alpha power are associated with different kinds of changes in the dynamics. Thus, the model parameters are useful dynamical biomarkers for spontaneous human alpha oscillations.

Gamma frailty model for linkage analysis with application to interval-censored migraine data.

For many diseases, it seems that the age at onset is genetically influenced. Therefore, the age-at-onset data are often collected in order to map the disease gene(s). The ages are often (right) censored or truncated, and therefore, many standard techniques for linkage analysis cannot be used. In this paper, we present a correlated frailty model for censored survival data of siblings. The model is used for testing heritability for the age at onset and linkage between the loci and the gene(s) that influence(s) the survival time. The model is applied to interval-censored migraine twin data. Heritability (obtained from the frailties rather than actual onset times) was estimated as 0.42; this value was highly significant. The highest lod score, a score of 1.9, was found at the end of chromosome 19.

Correcting missing-data bias in historical demography.

Studies on population history are often based on incomplete records of life histories. For instance, in studies using data obtained from family reconstitution, the date of death is right censored (by migration) and the censoring time is never observed. Several methods for the correction of mortality estimates are proposed in the literature, most of which first estimate the number of individuals at risk and then use standard techniques to estimate mortality. Other methods are based on statistical models. In this paper all methods are reviewed, and their merits are compared by applying them to simulated and to seventeenth-century data from the English parish of Reigate. An ad hoc method proposed by Ruggles performs reasonably well. Methods based on statistical models, provided they are sufficiently realistic, give comparable accuracy and allow the estimation of several other quantities of interest, such as the distribution of migration times.

Cross-platform array comparative genomic hybridization meta-analysis separates hematopoietic and mesenchymal from epithelial tumors.

A series of studies have been published that evaluate the chromosomal copy number changes of different tumor classes using array comparative genomic hybridization (array CGH); however, the chromosomal aberrations that distinguish the different tumor classes have not been fully characterized. Therefore, we performed a meta-analysis of different array CGH data sets in an attempt to classify samples tested across different platforms. As opposed to RNA expression, a common reference is used in dual channel CGH arrays: normal human DNA, theoretically facilitating cross-platform analysis. To this aim, cell line and primary cancer data sets from three different dual channel array CGH platforms obtained by four different institutes were integrated. The cell line data were used to develop preprocessing methods, which performed noise reduction and transformed samples into a common format. The transformed array CGH profiles allowed perfect clustering by cell line, but importantly not by platform or institute. The same preprocessing procedures used for the cell line data were applied to data from 373 primary tumors profiled by array CGH, including controls. Results indicated that there is no apparent feature related to the institute or platform and that array CGH allows for unambiguous cross-platform meta-analysis. Major clusters with common tissue origin were identified. Interestingly, tumors of hematopoietic and mesenchymal origins cluster separately from tumors of epithelial origin. Therefore, it can be concluded that chromosomal aberrations of tumors from hematopoietic and mesenchymal origin versus tumors of epithelial origin are distinct, and these differences can be picked up by meta-analysis of array CGH data. This suggests the possibility of prospectively using combined analysis of diverse copy number data sets for cancer subtype classification.

Simulation of liquid water using semiempirical Hamiltonians and the divide and conquer approach.

This work examines the ability of semiempirical methods to describe the structure of liquid water. Particularly, the standard AM1 and PM3 methods together with recently developed PM3-PIF and PM3-MAIS parametrizations have been considered. We perform molecular dynamics simulations for a system consisting of 64 or 216 water molecules in a periodic cubic box. The whole system is described quantum mechanically. Calculations with 64 molecules have been carried out using standard SCF techniques whereas calculations with 216 molecules have been done using the divide and conquer approach. This method has also been used in one simulation case with 64 molecules for test purposes. Within this scope, the molecular dynamics program ROAR have been coupled with a linear scaling semiempirical code (DivCon) implemented in a parallel MPI version. The predicted liquid water structure using either AM1 or PM3 is shown to be very poor due to well-known limitations of these methods describing hydrogen bonds. In contrast, PM3-PIF and PM3-MAIS calculations lead to results in reasonably good agreement with experimental data. The best results for the heat of vaporization are obtained with the PM3-PIF method. The average induced dipole moment of the water molecule in the liquid is underestimated by all semiempirical techniques, which seems to be related to the NDDO approximation and to the use of minimal basis sets. A brief discussion on charge-transfer effects in liquid water is also presented.

[Growth charts for height, weight and body-mass index of twins during infancy]. / Groeidiagrammen voor lengte, gewicht en 'body mass index' van tweelingen in de peutertijd.

OBJECTIVE: To determine the magnitude of the growth retardation in Dutch monozygotic and dizygotic twins during infancy in comparison with the Dutch reference growth charts for general population infants from 1997 and to construct reference growth charts for twins. DESIGN: Descriptive. METHOD: The growth of twins was studied using longitudinal data on over 4000 Dutch twin pairs from birth until 2.5 years of age. The LMS method was used to obtain growth charts for height, weight and body-mass index (BMI) for twin pairs during infancy. Centiles were estimated by the Box-Cox power curve (L), the median curve (M) and the coefficient of variation curve (S). RESULTS: From birth until the age of half a year, the average height and weight of twin pairs were at about the 10th percentile of the Dutch reference population. One year later this difference had decreased to about the 25th percentile, and when the twin pairs were between 1.5 and 2.5 years of age the difference was further decreased to the 35th percentile. The BMI deviated less from that of the reference population: during the first half a year the BMI of twin pairs was at about the 25th percentile. Subsequently, the BMI improved, but remained slightly below the median of the reference population at the age of about two years. Approximately half (50% for height, 58% for weight) of the growth retardation from birth until 1.5 years was attributable to gestational age. Between 1.5 years and 2.5 years of age, this difference was reduced to one third: 33% for both height and weight. Thus, a substantial part of the growth difference could not be explained by gestational age. CONCLUSION: Correcting for gestational age alone is not sufficient to make possible a comparison of the growth of twin pairs with the growth of general population infants. The development of twins can, however, be followed by means of the reference growth charts designed by the authors.

New developments in applying quantum mechanics to proteins.

Algorithmic improvements of quantum mechanical methodologies have increased our ability to study the electronic structure of fragments of a biomolecule (e.g. an enzyme active site) or entire biomolecules. Three main strategies have emerged as ways in which quantum mechanics can be applied to biomolecules. The supermolecule approach continues to be utilized, but it is slowly being replaced by the so-called coupled quantum mechanical/molecular mechanical methodologies. An exciting new direction is the continued development and application of linear-scaling quantum mechanical approaches to biomolecular systems.

An estimation of drag in front crawl swimming.

Propulsive arm forces of twelve elite male swimmers during a front crawl swimming-like activity were measured. The swimmers pushed off against grips which are attached to a 23 m tube at 0.8 m under the water surface. The tube was fixed to a force transducer. Since at constant speed, mean propulsive force equals mean drag force this method also provides the mean active drag on a moving swimmer. The mean propulsive force at a speed of v = 1.48 m s-1 appeared to be 53.2 +/- 5.8 N which is two to three times smaller than what is reported by other authors for active drag but which is in agreement with values reported for passive drag on a (towed) swimmer who is not moving. Discrepancies with indirect active drag measurements are discussed.