Bias from weak instruments may undermine the ability to estimate causal effects in instrumental variable regression (IVR). We present here a new approach to handling weak instrument bias through the application of a new type of instrumental variable coined 'Cross-Fitted Instrument' (CFI). CFI splits the data at random and estimates the impact of the instrument on the exposure in each partition. These estimates are then used to perform an IVR on each partition. We adapt CFI to the Mendelian randomization (MR) setting and term this adaptation 'Cross-Fitting for Mendelian Randomization' (CFMR). We show that, even when using weak instruments, CFMR is, at worst, biased towards the null, which makes it a conservative one-sample MR approach. In particular, CFMR remains conservative even when the two samples used to perform the MR analysis completely overlap, whereas current state-of-the-art approaches (e.g., MR RAPS) display substantial bias in this setting. Another major advantage of CFMR lies in its use of all of the available data to select genetic instruments, which maximizes statistical power, as opposed to traditional two-sample MR where only part of the data is used to select the instrument. Consequently, CFMR is able to enhance statistical power in consortia-led meta-analyses by enabling a conservative one-sample MR to be performed in each cohort prior to a meta-analysis of the results across all the cohorts. In addition, CFMR enables a cross-ethnic MR analysis by accounting for ethnic heterogeneity, which is particularly important in meta-analyses where the participating cohorts may have different ethnicities. To our knowledge, none of the current MR approaches can account for such heterogeneity. Finally, CFMR enables the application of MR to exposures that are either rare or difficult to measure, which would normally preclude their analysis in the regular two-sample MR setting.

MOTIVATION: Mendelian randomization is an epidemiological technique that uses genetic variants as instrumental variables to estimate the causal effect of a risk factor on an outcome. We consider a scenario in which causal estimates based on each variant in turn differ more strongly than expected by chance alone, but the variants can be divided into distinct clusters, such that all variants in the cluster have similar causal estimates. This scenario is likely to occur when there are several distinct causal mechanisms by which a risk factor influences an outcome with different magnitudes of causal effect. We have developed an algorithm MR-Clust that finds such clusters of variants, and so can identify variants that reflect distinct causal mechanisms. Two features of our clustering algorithm are that it accounts for differential uncertainty in the causal estimates, and it includes 'null' and 'junk' clusters, to provide protection against the detection of spurious clusters. RESULTS: Our algorithm correctly detected the number of clusters in a simulation analysis, outperforming methods that either do not account for uncertainty or do not include null and junk clusters. In an applied example considering the effect of blood pressure on coronary artery disease risk, the method detected four clusters of genetic variants. A post hoc hypothesis-generating search suggested that variants in the cluster with a negative effect of blood pressure on coronary artery disease risk were more strongly related to trunk fat percentage and other adiposity measures than variants not in this cluster. AVAILABILITY AND IMPLEMENTATION: MR-Clust can be downloaded from https://github.com/cnfoley/mrclust. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Abstract The contribution of local (“grassroots”) sporting clubs to their economies amounts to billions of dollars. These clubs typically rely on volunteers who use Internet platforms (such as websites and social media) to support their roles. Use of the Internet can assist these volunteers by facilitating improved information access, communication, and efficiency. Little is known about how local sporting clubs use this important information systems' function. This study extends Burgess' (2016) web presence pyramid model to examine factors leading to differences in Internet use by athletics and cricket clubs in the United Kingdom and Australia. The findings suggest that higher adoption levels of websites set up by clubs and social media and more sophisticated Internet usage are apparent in “upper” level (or well‐resourced) local clubs than in “lower” level clubs, but with some important variations (such as interventions by sport governing bodies) that may assist smaller clubs to adopt online platforms. Guidance on using the extended model in other contexts is offered, as is advice for clubs and sporting associations looking to improve their use of Internet platforms.

SUMMARY: PhenoScanner is a curated database of publicly available results from large-scale genetic association studies in humans. This online tool facilitates 'phenome scans', where genetic variants are cross-referenced for association with many phenotypes of different types. Here we present a major update of PhenoScanner ('PhenoScanner V2'), including over 150 million genetic variants and more than 65 billion associations (compared to 350 million associations in PhenoScanner V1) with diseases and traits, gene expression, metabolite and protein levels, and epigenetic markers. The query options have been extended to include searches by genes, genomic regions and phenotypes, as well as for genetic variants. All variants are positionally annotated using the Variant Effect Predictor and the phenotypes are mapped to Experimental Factor Ontology terms. Linkage disequilibrium statistics from the 1000 Genomes project can be used to search for phenotype associations with proxy variants. AVAILABILITY AND IMPLEMENTATION: PhenoScanner V2 is available at www.phenoscanner.medschl.cam.ac.uk.

We propose a novel multiple instance learning method to assess the visibility (visible/not visible) of the retinal nerve fiber layer (RNFL) in fundus camera images. Using only image-level labels, our approach learns to classify the images as well as to localize the RNFL visible regions. We transform the original feature space to a discriminative subspace, and learn a region-level classifier in that subspace. We propose a margin-based loss function to jointly learn this subspace and the region-level classifier. Experiments with a RNFL dataset containing 884 images annotated by two ophthalmologists give a system-annotator agreement (kappa values) of 0:73 and 0:72 respectively, with an inter-annotator agreement of 0:73. Our system agrees better with the more experienced annotator. Comparative tests with three public datasets (MESSIDOR and DR for diabetic retinopathy, UCSB for breast cancer) show that our novel MIL approach improves performance over the state-of-the-art. Our Matlab code is publicly available at https://github.com/ManiShiyam/Sub-category-classifiersfor- Multiple-Instance-Learning/wiki.

PhenoScanner is a curated database of publicly available results from large-scale genetic association studies. This tool aims to facilitate 'phenome scans', the cross-referencing of genetic variants with many phenotypes, to help aid understanding of disease pathways and biology. The database currently contains over 350 million association results and over 10 million unique genetic variants, mostly single nucleotide polymorphisms. It is accompanied by a web-based tool that queries the database for associations with user-specified variants, providing results according to the same effect and non-effect alleles for each input variant. The tool provides the option of searching for trait associations with proxies of the input variants, calculated using the European samples from 1000 Genomes and Hapmap. AVAILABILITY AND IMPLEMENTATION: PhenoScanner is available at www.phenoscanner.medschl.cam.ac.uk CONTACT: [email protected] information: Supplementary data are available at Bioinformatics online.

This article investigates ‘stage’ models that have been developed for researchers, practitioners and policymakers to explain how small businesses move from a basic to a sophisticated online presence and/or provide advice as to how they could do this. The main problem of these models is that small businesses do not necessarily develop their online presence in this manner. In addition, they do not consider that the online presence of most small businesses extends beyond their own website to the use of third party web portals, business directories and more recently social media websites. A new model, the web presence pyramid model, is thus proposed. The model represents the adoption levels of different categories of website features and does this in a non-linear manner, overcoming a limitation of stage models. A further contribution of the article is the classification of the web presence of small business industry sectors into new categories: Basic Web Presence; Added Value Websites; Online Database Websites and Payment Web Presence. A survey approach was used to conduct an online content analysis of the web presence of Australian small businesses, with the different types of web presences across industry sectors presented using the web presence pyramid model.

The wireless sensor network "macroscope" offers the potential to advance science by enabling dense temporal and spatial monitoring of large physical volumes. This paper presents a case study of a wireless sensor network that recorded 44 days in the life of a 70-meter tall redwood tree, at a density of every 5 minutes in time and every 2 meters in space. Each node measured air temperature, relative humidity, and photosynthetically active solar radiation. The network captured a detailed picture of the complex spatial variation and temporal dynamics of the microclimate surrounding a coastal redwood tree. This paper describes the deployed network and then employs a multi-dimensional analysis methodology to reveal trends and gradients in this large and previously-unobtainable dataset. An analysis of system performance data is then performed, suggesting lessons for future deployments.