The Mizon–Richard Encompassing Test for the Cox and Aalen Additive Hazards Models

Summary .   The Cox hazards model ( Cox, 1972 , Journal of the Royal Statistical Society, Series B 34, 187–220) for survival data is routinely used in many applied fields, sometimes, however, with too little emphasis on the fit of the model. A useful alternative to the Cox model is the Aalen additive hazards model ( Aalen, 1980 , in Lecture Notes in Statistics-2 , 1–25) that can easily accommodate time changing covariate effects. It is of interest to decide which of the two models that are most appropriate to apply in a given application. This is a nontrivial problem as these two classes of models are nonnested except only for special cases. In this article we explore the Mizon–Richard encompassing test for this particular problem. It turns out that it corresponds to fitting of the Aalen model to the martingale residuals obtained from the Cox regression analysis. We also consider a variant of this method, which relates to the proportional excess model ( Martinussen and Scheike, 2002 , Biometrika 89, 283–298). Large sample properties of the suggested methods under the two rival models are derived. The finite-sample properties of the proposed procedures are assessed through a simulation study. The methods are further applied to the well-known primary biliary cirrhosis data set.     

Urinary nucleic acid oxidation product levels show differential associations with pharmacological treatment in patients with type 2 diabetes

The relationship between RNA and DNA oxidation and pharmacological treatment has not been systematically investigated in patients with type 2 diabetes (T2D). We aimed to investigate the association between pharmacological treatments and levels of urinary markers of nucleic acid oxidation in T2D patients. Vejle Diabetes Biobank cohort data was nested into nationwide registry data. Multiple logistic regression was used to associate drug usage with risk of high (above median) RNA and DNA oxidation. Data from 2664 T2D patients (64% male, age range: 25–75) were included. Questionnaire-validated lipid lowering drug use was associated with low RNA oxidation (Odds ratio, OR 0.71, 95% CI: [0.59–0.87]). Insulin and non-specific antidiabetic drugs were associated with low DNA oxidation (insulin: OR 0.60, 95% CI [0.49–0.73]). Oral antidiabetics were associated with high DNA oxidation and RNA oxidation (OR 1.30, 95% CI [1.10–1.53] and OR 1.26, 95% CI [1.07–1.29]). Our findings indicate that diabetes-related drugs are associated with RNA and DNA oxidation and further studies are required to determine causality in T2D patients.     

Modelling interaction sites in protein domains with interaction profile hidden Markov models

MOTIVATION: Due to the growing number of completely sequenced genomes, functional annotation of proteins becomes a more and more important issue. Here, we describe a method for the prediction of sites within protein domains, which are part of protein-ligand interactions. As recently demonstrated, these sites are not trivial to detect because of a varying degree of conservation of their location and type within a domain family. RESULTS: The developed method for the prediction of protein-ligand interaction sites is based on a newly defined interaction profile hidden Markov model (ipHMM) topology that takes structural and sequence data into account. It is based on a homology search via a posterior decoding algorithm that yields probabilities for interacting sequence positions and inherits the efficiency and the power of the profile hidden Markov model (pHMM) methodology. The algorithm enhances the quality of interaction site predictions and is a suitable tool for large scale studies, which was already demonstrated for pHMMs. AVAILABILITY: The MATLAB-files are available on request from the first author.     

Rapid microstructural plasticity in the cortical semantic network following a short language learning session

Despite the clear importance of language in our life, our vital ability to quickly and effectively learn new words and meanings is neurobiologically poorly understood. Conventional knowledge maintains that language learning—especially in adulthood—is slow and laborious. Furthermore, its structural basis remains unclear. Even though behavioural manifestations of learning are evident near instantly, previous neuroimaging work across a range of semantic categories has largely studied neural changes associated with months or years of practice. Here, we address rapid neuroanatomical plasticity accompanying new lexicon acquisition, specifically focussing on the learning of action-related language, which has been linked to the brain’s motor systems. Our results show that it is possible to measure and to externally modulate (using transcranial magnetic stimulation (TMS) of motor cortex) cortical microanatomic reorganisation after mere minutes of new word learning. Learning-induced microstructural changes, as measured by diffusion kurtosis imaging (DKI) and machine learning-based analysis, were evident in prefrontal, temporal, and parietal neocortical sites, likely reflecting integrative lexico-semantic processing and formation of new memory circuits immediately during the learning tasks. These results suggest a structural basis for the rapid neocortical word encoding mechanism and reveal the causally interactive relationship of modal and associative brain regions in supporting learning and word acquisition.

This combined neuroimaging and brain stimulation study reveals rapid and distributed microstructural plasticity after a single immersive language learning session, demonstrating the causal relevance of the motor cortex in encoding the meaning of novel action words.     

DNA double-strand break repair pathways, chromosomal rearrangements and cancer

Chromosomal rearrangements, which can lead to oncogene activation and tumour suppressor loss, are a hallmark of cancer cells. Such outcomes can result from both the repair and misrepair of DNA ends, which arise from a variety of lesions including DNA double strand breaks (DSBs), collapsed replication forks and dysfunctional telomeres. Here we review the mechanisms by which non-homologous end joining (NHEJ) and homologous recombination (HR) repair pathways can both promote chromosomal rearrangements and also suppress them in response to such lesions, in accordance with their increasingly recognised tumour suppressor function. Further, we consider how chromosomal rearrangements, together with a modular approach towards understanding their etiology, may be exploited for cancer therapy.     

Close linkage between X-linked ectodermal dysplasia and a cloned DNA sequence detecting a two allele restriction fragment length polymorphism in the region Xp11-q12

Summary EDA (ectodermal dysplasia, anhidrotic) is an X-linked recessive disorder characterized by hypohidrosis, hypoor anodontia, and hypotrichosis. A possible linkage between the gene for EDA and a number of restriction fragment length polymorphisms (RFLPs) spread over the X chromosome was investigated in two Danish families segregating EDA. No recombination between the gene for EDA and our probe pTAK8, which detects a two allele polymorphism in the region Xp11-q12, was found in nine informative meiotic events (seven of which are phase known), giving a maximal lod score of 2.41 at a recombination fraction of 0.00. This juxtacentromeric location of the gene for EDA agrees well with the linkage data obtained with the other markers used in this study.     

Conquered from the Deep Sea? A New Deep-Sea Isopod Species from the Antarctic Shelf Shows Pattern of Recent Colonization

The Amundsen Sea, Antarctica, is amongst the most rapidly changing environments of the world. Its benthic inhabitants are barely known and the BIOPEARL 2 project was one of the first to biologically explore this region. Collected during this expedition, Macrostylis roaldi sp. nov. is described as the first isopod discovered on the Amundsen-Sea shelf. Amongst many characteristic features, the most obvious characters unique for M. roaldi are the rather short pleotelson and short operculum as well as the trapezoid shape of the pleotelson in adult males. We used DNA barcodes (COI) and additional mitochondrial markers (12S, 16S) to reciprocally illuminate morphological results and nucleotide variability. In contrast to many other deep-sea isopods, this species is common and shows a wide distribution. Its range spreads from Pine Island Bay at inner shelf right to the shelf break and across 1,000 m bathymetrically. Its gene pool is homogenized across space and depth. This is indicative for a genetic bottleneck or a recent colonization history. Our results suggest further that migratory or dispersal capabilities of some species of brooding macrobenthos have been underestimated. This might be relevant for the species’ potential to cope with effects of climate change. To determine where this species could have survived the last glacial period, alternative refuge possibilities are discussed.