A Poly-algorithmic Approach to Quantifier Elimination

Cylindrical Algebraic Decomposition (CAD) was the first practical means for doing real quantifier elimination (QE), and is still a major method, with many improvements since Collins' original method. Nevertheless, its complexity is inherently doubly exponential in the number of variables. Where applicable, virtual term substitution (VTS) is more effective, turning a QE problem in $n$ variables to one in $n-1$ variables in one application, and so on. Hence there is scope for hybrid methods: doing VTS where possible then using CAD. This paper describes such a poly-algorithmic implementation, based on the second author's Ph.D. thesis. The version of CAD used is based on a new implementation of Lazard's recently-justified method, with some improvements to handle equational constraints

Non-linear Real Arithmetic Benchmarks derived from Automated Reasoning in Economics

We consider problems originating in economics that may be solved automatically using mathematical software. We present and make freely available a new benchmark set of such problems. The problems have been shown to fall within the framework of non-linear real arithmetic, and so are in theory soluble via Quantifier Elimination (QE) technology as usually implemented in computer algebra systems. Further, they all can be phrased in prenex normal form with only existential quantifiers and so are also admissible to those Satisfiability Module Theory (SMT) solvers that support the QF_NRA. There is a great body of work considering QE and SMT application in science and engineering, but we demonstrate here that there is potential for this technology also in the social sciences.Comment: To appear in Proc. SC-Square 2018. Dataset described is hosted by Zenodo at: https://doi.org/10.5281/zenodo.1226892 . arXiv admin note: substantial text overlap with arXiv:1804.1003

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

'On Fast Matrix Inversion' Cancellations Demonstration Worksheet

A Maple (2018) worksheet created to demonstrate cancellations found in the accompanying paper 'On Fast Matrix Inversion by Fast Matrix Multiplication', written by Zak Tonks and published on ArXiV. This worksheet also describes and demonstrates additional effects mentioned in the paper, such as the use of padding on the new object "Delta" in the fraction free case.Worksheet written, run, and saved by Zak Tonks, November 2018 using Maple 2018.0.Written and run using Maple 2018.0, running on a PC running Windows 10 Pro, i5-2500 processor 3.3GHz, 16GB RAM. Worksheet presented for viewing at least, but one should be able to run successfully in a few minutes on any processor at least as good. Licensed copy of Maple required to view, tested and verified working in earliest version Maple 2017, but may run in earlier versions as no particular packages used