Analysis of “big data” frequently involves statistical comparison of millions of competing hypotheses to discover hidden processes underlying observed patterns of data, for example, in the search for ...genetic determinants of disease in genome-wide association studies (GWAS). Controlling the familywise error rate (FWER) is considered the strongest protection against false positives but makes it difficult to reach the multiple testing-corrected significance threshold. Here, I introduce the harmonic mean p-value (HMP), which controls the FWER while greatly improving statistical power by combining dependent tests using generalized central limit theorem. I show that the HMP effortlessly combines information to detect statistically significant signals among groups of individually nonsignificant hypotheses in examples of a human GWAS for neuroticism and a joint human–pathogen GWAS for hepatitis C viral load. The HMP simultaneously tests all ways to group hypotheses, allowing the smallest groups of hypotheses that retain significance to be sought. The power of the HMP to detect significant hypothesis groups is greater than the power of the Benjamini–Hochberg procedure to detect significant hypotheses, although the latter only controls the weaker false discovery rate (FDR). The HMP has broad implications for the analysis of large datasets, because it enhances the potential for scientific discovery.
Recombination is an important evolutionary force in bacteria, but it remains challenging to reconstruct the imports that occurred in the ancestry of a genomic sample. Here we present ClonalFrameML, ...which uses maximum likelihood inference to simultaneously detect recombination in bacterial genomes and account for it in phylogenetic reconstruction. ClonalFrameML can analyse hundreds of genomes in a matter of hours, and we demonstrate its usefulness on simulated and real datasets. We find evidence for recombination hotspots associated with mobile elements in Clostridium difficile ST6 and a previously undescribed 310kb chromosomal replacement in Staphylococcus aureus ST582. ClonalFrameML is freely available at http://clonalframeml.googlecode.com/.
We quantify how sensitive is migration by star scientists to changes in personal and business tax differentials across states. We uncover large, stable, and precisely estimated effects of personal ...and corporate taxes on star scientists' migration patterns. The long-run elasticity of mobility relative to taxes is 1.8 for personal income taxes, 1.9 for state corporate income tax, and — 1.7 for the investment tax credit. While there are many other factors that drive when innovative individuals and innovative companies decide to locate, there are enough firms and workers on the margin that state taxes matter.
Generation time varies widely across organisms and is an important factor in the life cycle, life history and evolution of organisms. Although the doubling time (DT) has been estimated for many ...bacteria in the laboratory, it is nearly impossible to directly measure it in the natural environment. However, an estimate can be obtained by measuring the rate at which bacteria accumulate mutations per year in the wild and the rate at which they mutate per generation in the laboratory. If we assume the mutation rate per generation is the same in the wild and in the laboratory, and that all mutations in the wild are neutral, an assumption that we show is not very important, then an estimate of the DT can be obtained by dividing the latter by the former. We estimate the DT for five species of bacteria for which we have both an accumulation and a mutation rate estimate. We also infer the distribution of DTs across all bacteria from the distribution of the accumulation and mutation rates. Both analyses suggest that DTs for bacteria in the wild are substantially greater than those in the laboratory, that they vary by orders of magnitude between different species of bacteria and that a substantial fraction of bacteria double very slowly in the wild.
The proliferation of R&D tax incentives among U.S. states in recent decades raises two questions: (i) Are these tax incentives effective in increasing in-state R&D? (ii) How much of any increase is ...due to R&D being drawn away from other states? This paper answers (i) "yes" and (ii) "nearly all." The paper estimates an augmented R&D factor demand model using state panel data from 1981 to 2004. I estimate that the long-run elasticity of in-state R&D with respect to the in-state user cost is about -2.5, while its elasticity with respect to out-of-state user costs is about +2.5, suggesting a zero-sum game among states.
Measuring news sentiment Shapiro, Adam Hale; Sudhof, Moritz; Wilson, Daniel J.
Journal of econometrics,
06/2022, Volume:
228, Issue:
2
Journal Article
Peer reviewed
Open access
This paper demonstrates state-of-the-art text sentiment analysis tools while developing a new time-series measure of economic sentiment derived from economic and financial newspaper articles from ...January 1980 to April 2015. We compare the predictive accuracy of a large set of sentiment analysis models using a sample of articles that have been rated by humans on a positivity/negativity scale. The results highlight the gains from combining existing lexicons and from accounting for negation. We also generate our own sentiment-scoring model, which includes a new lexicon built specifically to capture the sentiment in economic news articles. This model is shown to have better predictive accuracy than existing “off-the-shelf” models. Lastly, we provide two applications to the economic research on sentiment. First, we show that daily news sentiment is predictive of movements of survey-based measures of consumer sentiment. Second, motivated by Barsky and Sims (2012), we estimate the impulse responses of macroeconomic variables to sentiment shocks, finding that positive sentiment shocks increase consumption, output, and interest rates and dampen inflation.
Much of the science underpinning the global response to the COVID-19 pandemic lies in the soft matter domain. Coronaviruses are composite particles with a core of nucleic acids complexed to proteins ...surrounded by a protein-studded lipid bilayer shell. A dominant route for transmission is
via
air-borne aerosols and droplets. Viral interaction with polymeric body fluids, particularly mucus, and cell membranes controls their infectivity, while their interaction with skin and artificial surfaces underpins cleaning and disinfection and the efficacy of masks and other personal protective equipment. The global response to COVID-19 has highlighted gaps in the soft matter knowledge base. We survey these gaps, especially as pertaining to the transmission of the disease, and suggest questions that can (and need to) be tackled, both in response to COVID-19 and to better prepare for future viral pandemics.
Much of the science underpinning the global response to the COVID-19 pandemic lies in the soft matter domain.
Decisions to continue or suspend therapy with immune checkpoint inhibitors are commonly guided by tumor dynamics seen on serial imaging. However, immunotherapy responses are uniquely challenging to ...interpret because tumors often shrink slowly or can appear transiently enlarged due to inflammation. We hypothesized that monitoring tumor cell death in real time by quantifying changes in circulating tumor DNA (ctDNA) levels could enable early assessment of immunotherapy efficacy.
We compared longitudinal changes in ctDNA levels with changes in radiographic tumor size and with survival outcomes in 28 patients with metastatic non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitor therapy. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma using a multigene next-generation sequencing assay. We defined a ctDNA response as a >50% decrease in mutant allele fraction from baseline, with a second confirmatory measurement.
Strong agreement was observed between ctDNA response and radiographic response (Cohen's kappa, 0.753). Median time to initial response among patients who achieved responses in both categories was 24.5 days by ctDNA versus 72.5 days by imaging. Time on treatment was significantly longer for ctDNA responders versus nonresponders (median, 205.5 vs. 69 days;
< 0.001). A ctDNA response was associated with superior progression-free survival hazard ratio (HR), 0.29; 95% CI, 0.09-0.89;
= 0.03, and superior overall survival (HR, 0.17; 95% CI, 0.05-0.62;
= 0.007).
A drop in ctDNA level is an early marker of therapeutic efficacy and predicts prolonged survival in patients treated with immune checkpoint inhibitors for NSCLC.
.
Abstract
The sequencing and comparative analysis of a collection of bacterial genomes from a single species or lineage of interest can lead to key insights into its evolution, ecology or ...epidemiology. The tool of choice for such a study is often to build a phylogenetic tree, and more specifically when possible a dated phylogeny, in which the dates of all common ancestors are estimated. Here, we propose a new Bayesian methodology to construct dated phylogenies which is specifically designed for bacterial genomics. Unlike previous Bayesian methods aimed at building dated phylogenies, we consider that the phylogenetic relationships between the genomes have been previously evaluated using a standard phylogenetic method, which makes our methodology much faster and scalable. This two-step approach also allows us to directly exploit existing phylogenetic methods that detect bacterial recombination, and therefore to account for the effect of recombination in the construction of a dated phylogeny. We analysed many simulated datasets in order to benchmark the performance of our approach in a wide range of situations. Furthermore, we present applications to three different real datasets from recent bacterial genomic studies. Our methodology is implemented in a R package called BactDating which is freely available for download at https://github.com/xavierdidelot/BactDating.
De-esterification of homogalacturonan (HG) is thought to stiffen pectin gels and primary cell walls by increasing calcium cross-linking between HG chains. Contrary to this idea, recent studies found ...that HG de-esterification correlated with reduced stiffness of living tissues, measured by surface indentation. The physical basis of such apparent wall softening is unclear, but possibly involves complex biological responses to HG modification. To assess the direct physical consequences of HG de-esterification on wall mechanics without such complications, we treated isolated onion (Allium cepa) epidermal walls with pectin methylesterase (PME) and assessed wall biomechanics with indentation and tensile tests. In nanoindentation assays, PME action softened the wall (reduced the indentation modulus). In tensile force/extension assays, PME increased plasticity, but not elasticity. These softening effects are attributed, at least in part, to increased electrostatic repulsion and swelling of the wall after PME treatment. Despite softening and swelling upon HG de-esterification, PME treatment alone failed to induce cell wall creep. Instead, acid-induced creep, mediated by endogenous α-expansin, was reduced. We conclude that HG de-esterification physically softens the onion wall, yet reduces expansin-mediated wall extensibility.
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