Large-Scale Differentiable Causal Discovery of Factor Graphs

A common theme in causal inference is learning causal relationships between observed variables, also known as causal discovery. This is usually a daunting task, given the large number of candidate causal graphs and the combinatorial nature of the search space. Perhaps for this reason, most research has so far focused on relatively small causal graphs, with up to hundreds of nodes. However, recent advances in fields like biology enable generating experimental data sets with thousands of interventions followed by rich profiling of thousands of variables, raising the opportunity and urgent need for large causal graph models. Here, we introduce the notion of factor directed acyclic graphs (f-DAGs) as a way to restrict the search space to non-linear low-rank causal interaction models. Combining this novel structural assumption with recent advances that bridge the gap between causal discovery and continuous optimization, we achieve causal discovery on thousands of variables. Additionally, as a model for the impact of statistical noise on this estimation procedure, we study a model of edge perturbations of the f-DAG skeleton based on random graphs and quantify the effect of such perturbations on the f-DAG rank. This theoretical analysis suggests that the set of candidate f-DAGs is much smaller than the whole DAG space and thus may be more suitable as a search space in the high-dimensional regime where the underlying skeleton is hard to assess. We propose Differentiable Causal Discovery of Factor Graphs (DCD-FG), a scalable implementation of -DAG constrained causal discovery for high-dimensional interventional data. DCD-FG uses a Gaussian non-linear low-rank structural equation model and shows significant improvements compared to state-of-the-art methods in both simulations as well as a recent large-scale single-cell RNA sequencing data set with hundreds of genetic interventions.Comment: 33 pages, 12 figure

A novel ‘triple drawdown’ method highlights deficiencies in invasive alien crayfish survey and control techniques

Freshwater crayfish can be successful invaders that threaten native biota and aquatic ecosystems in numerous countries worldwide. Nonetheless, the inability of conventional crayfish survey techniques like trapping and handsearching to yield quantitative population data has limited the understanding of crayfish invasion biology and associated ecological impacts. Here, we employed a novel ‘triple drawdown’ (TDD) method to sample invasive populations of signal crayfish Pacifastacus leniusculus in a headwater stream in Northern England. The method was compared with conventional techniques of trapping and handsearching. The TDD method proved to be an effective technique with high capture efficiency, reporting signal crayfish densities from 20.5 to 110.4 animals/m2 at our study sites. These numbers exceed any previous estimates for similar streams. The TDD showed the vast majority of individuals across all sites were juvenile or sub‐adult (<26 mm CL), with only 2.3% of the population large enough (≥35 mm CL) to be caught in standard traps. Synthesis and applications. The triple drawdown (TDD) method demonstrates strong inefficiencies and biases in conventional crayfish survey and management techniques. Trapping is not recommended for representative sampling or control of juvenile dominated populations. TDDs, which can be adapted and modified to operate in multiple habitat types and freshwater systems, generate robust quantitative data on invasive crayfish population demographics in situ. This can advance our understanding of the biology of an important invader of freshwater systems around the world. Obtaining this data prior and post‐intervention is fundamental to evaluate invasive crayfish management, and we recommend the TDD method to assess the effectiveness of future control measures

Pectobacterium parvum sp. nov., having a Salmonella SPI-1-like Type III secretion system and low virulence

Corrigendum: Pectobacterium parvum sp. nov., having a Salmonella SPI-1-like Type III secretion system and low virulence. Pages: 2959-2959. https://doi.org/10.1099/ijsem.0.004111Pectobacterium strains isolated from potato stems in Finland, Poland and the Netherlands were subjected to polyphasic analyses to characterize their genomic and phenotypic features. Phylogenetic analysis based on 382 core proteins showed that the isolates clustered closest to Pectobacterium polaris but could be divided into two clades. Average nucleotide identity (ANI) analysis revealed that the isolates in one of the clades included the P. polaris type strain, whereas the second Glade was at the border of the species P. polaris with a 96 % ANI value. In silico genome-to-genome comparisons between the isolates revealed values below 70%, patristic distances based on 1294 core proteins were at the level observed between closely related Pectobacterium species, and the two groups of bacteria differed in genome size, G+C content and results of amplified fragment length polymorphism and Biolog analyses. Comparisons between the genomes revealed that the isolates of the atypical group contained SPI-1-type Type III secretion island and genes coding for proteins known for toxic effects on nematodes or insects, and lacked many genes coding for previously characterized virulence determinants affecting rotting of plant tissue by soft rot bacteria. Furthermore, the atypical isolates could be differentiated from P. polaris by their low virulence, production of antibacterial metabolites and a citrate-negative phenotype. Based on the results of a polyphasic approach including genome-to-genome comparisons, biochemical and virulence assays, presented in this report, we propose delineation of the atypical isolates as a novel species Pectobacterium parvum, for which the isolate s0421(T) (CFBP 8630(T)=LMG 30828(T)) is suggested as a type strain.Peer reviewe

Icy thermometers : quantifying the impact of volcanic heat on glacier elevation

ACKNOWLEDGEMENTS This project was supported by the NERC Global Partnerships Seedcorn grant NE/W003724/1 and the Leverhulme Trust Research Project RPG-2019-093. We thank Kevin A. Reath for support in analysing volcanic thermal anomalies. A.G.P. and M.E.P. were partly supported by the NASA Science Mission Directorate Earth Surface and Interior grant 80NSSC21K0842. J.J. was supported by the NERC Quadrat Doctoral Training Partnership. We express our gratitude to John Smellie and an anonymous reviewer for fruitful feedback which greatly improved the manuscript.Peer reviewedPostprin

Cost-effectiveness modelling of use of urea breath test for the management of Helicobacter pylori-related dyspepsia and peptic ulcer in the UK.

Clinical data comparing diagnostic strategies in the management of Helicobacter pylori-associated diseases are limited. Invasive and noninvasive diagnostic tests for detecting H. pylori infection are used in the clinical care of patients with dyspeptic symptoms. Modelling studies might help to identify the most cost-effective strategies. The objective of the study is to assess the cost-effectiveness of a 'test-and-treat' strategy with the urea breath test (UBT) compared with other strategies, in managing patients with H. pylori-associated dyspepsia and preventing peptic ulcer in the UK. Cost-effectiveness models compared four strategies: 'test-and-treat' with either UBT or faecal antigen test (FAT), 'endoscopy-based strategy' and 'symptomatic treatment'. A probabilistic cost-effectiveness analysis was performed using a simulation model in order to identify probabilities and costs associated with relief of dyspepsia symptoms (over a 4-week time horizon) and with prevention of peptic ulcers (over a 10-year time horizon). Clinical and cost inputs to the model were derived from routine medical practice in the UK. For relief of dyspepsia symptoms, 'test-and-treat' strategies with either UBT (€526/success) and FAT (€518/success) were the most cost-effective strategies compared with 'endoscopy-based strategy' (€1317/success) and 'symptomatic treatment' (€1 029/success). For the prevention of peptic ulcers, 'test-and-treat' strategies with either UBT (€208/ulcer avoided/year) or FAT (€191/ulcer avoided/year) were the most cost-effective strategies compared with 'endoscopy-based strategy' (€717/ulcer avoided/year) and 'symptomatic treatment' (€651/ulcer avoided/year) (1 EUR=0,871487 GBP at the time of the study). 'Test-and-treat' strategies with either UBT or FAT are the most cost-effective medical approaches for the management of H. pylori-associated dyspepsia and the prevention of peptic ulcer in the UK. A 'test-and-treat' strategy with UBT has comparable cost-effectiveness outcomes to the current standard of care using FAT in the UK

Colon hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in individuals with irritable bowel syndrome

Background & Aims: Poorly digested, fermentable carbohydrates may induce symptoms of irritable bowel syndrome (IBS), via unclear mechanisms. We performed a randomized trial with magnetic resonance imaging (MRI) analysis to investigate correlations between symptoms and changes in small and large bowel contents following oral challenge. Methods: We performed a 3-period crossover study of 29 adult patients with IBS (based on Rome III criteria, with symptoms of abdominal pain or discomfort for at least 2 days/week) and reported bloating. In parallel we performed the same study of 29 healthy individuals (controls). Studies were performed in the United Kingdom from January 2013 through February 2015. On 3 separate occasions (at least 7 days apart), subjects were given a 500 ml drink containing 40 g of carbohydrate (glucose in the first period, fructose in the second, and inulin in the third, in a random order). Levels of breath hydrogen were measured and intestinal content was assessed by MRI before and at various time points after consumption of each drink. Symptoms were determined based on subjects’ responses to the Hospital Anxiety and Depression Scale questionnaire and the Patient Health Questionnaire-15. The primary endpoint was whether participants had a clinically important symptom response during the 300 minutes following consumption of the drink. Results: More patients with IBS reached the pre-defined symptom threshold after intake of inulin (13/29) or fructose (11/29) than glucose (6/29). Symptoms peaked sooner after intake of fructose than inulin. Fructose increased small bowel water content in both patients and controls whereas inulin increased colonic volume and gas in both. Fructose and inulin increased breath hydrogen levels in both groups, compared to glucose; fructose produced an earlier increase than inulin. Controls had lower symptom scores during the period after drink consumption than patients with IBS, despite similar MRI parameters and breath hydrogen responses. In patients who reached the symptom threshold after inulin intake, peak symptom intensity correlated with peak colonic gas (r = 0.57; P<0.05). Changes in MRI features and peak breath hydrogen levels were similar in patients who did and did not reach symptom threshold. Conclusions: Patients with IBS and healthy individuals without IBS (controls) have similar physiological responses following intake of fructose or inulin; patients more frequently report symptoms after inulin than controls. In patients with a response to inulin, symptoms relate to levels of intra-luminal gas, but peak gas levels do not differ significantly between responders, non-responders or controls. This indicates that colonic hypersensitivity to distension, rather than excessive gas production, produces carbohydrate-related symptoms in patients with IBS. Clinicaltrials.gov no: NCT0177685

Invariant measures for stochastic nonlinear beam and wave equations

Existence of an invariant measure for a stochastic extensible beam equation and for a stochastic damped wave equation with polynomial nonlinearities is proved. It is shown first that the corresponding transition semigroups map the space of all bounded sequentially weakly continuous functions on the state space into itself and then by a Lyapunov functions approach solutions bounded in probability are found