Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data

Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets

A retrospective and agenda for future research on Chinese outward foreign direct investment

Our original paper “The determinants of Chinese Outward Foreign Direct Investment” was the first theoretically based empirical analysis of the phenomenon. It utilised internalisation theory to show that Chinese state-owned firms reacted to home country market imperfections to surmount barriers to foreign entry arising from naivety and the lack of obvious ownership advantages, leveraging institutional factors including favourable policy stimuli. This special theory explained outward foreign direct investment (OFDI) but provided surprises. These included the apparent appetite for risk evinced by these early investors, causing us to conjecture that domestic market imperfections, particularly in the domestic capital market, might be responsible. The article stimulated a massive subsequent, largely successful, research effort on emerging country multinationals. In this Retrospective article we review some of the main strands of research that ensued, for the insight they offer for the theme of our commentary. Our theme is that theoretical development can only come through embracing yet more challenging, different, and new contexts, and we make suggestions for future research directions

Preserving Madagascar's Natural Heritage: The Importance of Keeping the Island's Vertebrate Fossils in the Public Domain

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Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis

Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-D-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level

Mitochondrial and nuclear genes suggest that stony corals are monophyletic but most families of stony corals are not (Order Scleractinia, Class Anthozoa, Phylum Cnidaria)

Modern hard corals (Class Hexacorallia; Order Scleractinia) are widely studied because of their fundamental role in reef building and their superb fossil record extending back to the Triassic. Nevertheless, interpretations of their evolutionary relationships have been in flux for over a decade. Recent analyses undermine the legitimacy of traditional suborders, families and genera, and suggest that a non-skeletal sister clade (Order Corallimorpharia) might be imbedded within the stony corals. However, these studies either sampled a relatively limited array of taxa or assembled trees from heterogeneous data sets. Here we provide a more comprehensive analysis of Scleractinia (127 species, 75 genera, 17 families) and various outgroups, based on two mitochondrial genes (cytochrome oxidase I, cytochrome b), with analyses of nuclear genes (ßtubulin, ribosomal DNA) of a subset of taxa to test unexpected relationships. Eleven of 16 families were found to be polyphyletic. Strikingly, over one third of all families as conventionally defined contain representatives from the highly divergent "robust" and "complex" clades. However, the recent suggestion that corallimorpharians are true corals that have lost their skeletons was not upheld. Relationships were supported not only by mitochondrial and nuclear genes, but also often by morphological characters which had been ignored or never noted previously. The concordance of molecular characters and more carefully examined morphological characters suggests a future of greater taxonomic stability, as well as the potential to trace the evolutionary history of this ecologically important group using fossils

Competition-based model of pheromone component ratio detection in the moth

For some moth species, especially those closely interrelated and sympatric, recognizing a specific pheromone component concentration ratio is essential for males to successfully locate conspecific females. We propose and determine the properties of a minimalist competition-based feed-forward neuronal model capable of detecting a certain ratio of pheromone components independently of overall concentration. This model represents an elementary recognition unit for the ratio of binary mixtures which we propose is entirely contained in the macroglomerular complex (MGC) of the male moth. A set of such units, along with projection neurons (PNs), can provide the input to higher brain centres. We found that (1) accuracy is mainly achieved by maintaining a certain ratio of connection strengths between olfactory receptor neurons (ORN) and local neurons (LN), much less by properties of the interconnections between the competing LNs proper. An exception to this rule is that it is beneficial if connections between generalist LNs (i.e. excited by either pheromone component) and specialist LNs (i.e. excited by one component only) have the same strength as the reciprocal specialist to generalist connections. (2) successful ratio recognition is achieved using latency-to-first-spike in the LN populations which, in contrast to expectations with a population rate code, leads to a broadening of responses for higher overall concentrations consistent with experimental observations. (3) when longer durations of the competition between LNs were observed it did not lead to higher recognition accuracy

South China Sea hydrological changes and Pacific Walker Circulation variations over the last millennium

© Macmillan Publishers Limited, 2011. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 2 (2011): 293, doi:10.1038/ncomms1297.The relative importance of north–south migrations of the intertropical convergence zone (ITCZ) versus El Niño-Southern Oscillation and its associated Pacific Walker Circulation (PWC) variability for past hydrological change in the western tropical Pacific is unclear. Here we show that north–south ITCZ migration was not the only mechanism of tropical Pacific hydrologic variability during the last millennium, and that PWC variability profoundly influenced tropical Pacific hydrology. We present hydrological reconstructions from Cattle Pond, Dongdao Island of the South China Sea, where multi-decadal rainfall and downcore grain size variations are correlated to the Southern Oscillation Index during the instrumental era. Our downcore grain size reconstructions indicate that this site received less precipitation during relatively warm periods, AD 1000–1400 and AD 1850–2000, compared with the cool period (AD 1400–1850). Including our new reconstructions in a synthesis of tropical Pacific records results in a spatial pattern of hydrologic variability that implicates the PWC.This work was supported by the Natural Science Foundation of China (NSFC) (40730107) and the Major State Basic Research Development Program of China (973 Program) (No.2010CB428902). DWO acknowledges support from the US NSF