The power of effective study design in animal Experimentation: Exploring the statistical and ethical implications of asking multiple questions of a data set

One of the chief advantages of using highly standardised biological models including model organisms is that multiple variables can be precisely controlled so that the variable of interest is more easily studied. However, such an approach often obscures effects in sub-populations resulting from natural population heterogeneity. Efforts to expand our fundamental understanding of multiple sub-populations are in progress. However, such stratified or personalised approaches require fundamental modifications of our usual study designs that should be implemented in Brain, Behavior and Immunity (BBI) research going forward. Here we explore the statistical feasibility of asking multiple questions (including incorporating sex) within the same experimental cohort using statistical simulations of real data. We illustrate and discuss the large explosion in sample numbers necessary to detect effects with appropriate power for every additional question posed using the same data set. This exploration highlights the strong likelihood of type II errors (false negatives) for standard data and type I errors when dealing with complex genomic data, where studies are too under-powered to appropriately test these interactions. We show this power may differ for males and females in high throughput data sets such as RNA sequencing. We offer a rationale for the use of alternative experimental and statistical strategies based on interdisciplinary insights and discuss the realworld implications of increasing the complexities of our experimental designs, and the implications of not attempting to alter our experimental designs going forward.R.A. Ankeny, A.L. Whittaker, M. Ryan, J. Boer, M. Plebanski, J. Tuke, S.J. Spence

Modelling the influence of plasticity induced softening on the low cycle fatigue and crack propagation behaviour of a nickel-based superalloy

Cyclic hysteresis loops generated during high-temperature, isothermal, low-cycle fatigue testing of the nickel-based superalloy RR1000 revealed a gradual decrease in elastic modulus of up to 25 % compared to the initial value in dependence of the accumulated plastic strain. Based on the experimental observations, a material model was developed and implemented within a finite element solver to investigate the effect of degrading stiffness on crack growth laws and crack growth predictions. It was shown that the stress intensity factor diminished by 6 to 8 % and crack growth rates were 14 to 20 % higher when stiffness degradation was accounted for.Funding Agencies|European Union [686600]</p

Phenomenology of the Lense-Thirring effect in the Solar System

Recent years have seen increasing efforts to directly measure some aspects of the general relativistic gravitomagnetic interaction in several astronomical scenarios in the solar system. After briefly overviewing the concept of gravitomagnetism from a theoretical point of view, we review the performed or proposed attempts to detect the Lense-Thirring effect affecting the orbital motions of natural and artificial bodies in the gravitational fields of the Sun, Earth, Mars and Jupiter. In particular, we will focus on the evaluation of the impact of several sources of systematic uncertainties of dynamical origin to realistically elucidate the present and future perspectives in directly measuring such an elusive relativistic effect.Comment: LaTex, 51 pages, 14 figures, 22 tables. Invited review, to appear in Astrophysics and Space Science (ApSS). Some uncited references in the text now correctly quoted. One reference added. A footnote adde

Forest Biodiversity Assessment in Peruvian Andean Montane Cloud Forest

Cloud forests are unusual and fragile habitats, being one of the least studied and least understood ecosystems. The tropical Andean dominion is considered one of the most significant places in the world as rega rds biological diversity, with a very high level of endemism. The biodiversity was analysed in an isolated remnant area of a tropical montane cloud forest known as the ?Bosque de Neblina de Cuyas?, in the North of the Peruvian Andean range. Composition, structure and dead wood were measured or estimated. The values obtained were compared with other cloud forests. The study revealed a high level of forest biodiversity, although the level of biodiversity differs from one area to another: in the inner areas, where human pressure is almost inexistent, the biodiversity values increase. The high species richness and the low dominance among species bear testimony to this montane cloud forest as a real enclave of biodiversity

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation