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

Bug hunting with false negatives

Safe data abstractions are widely used for verification purposes. Positive verification results can be transferred from the abstract to the concrete system. When a property is violated in the abstract system, one still has to check whether a concrete violation scenario exists. However, even when the violation scenario is not reproducible in the concrete system (a false negative), it may still contain information on possible sources of bugs.\ud Here, we propose a bug hunting framework based on abstract violation scenarios. We first extract a violation pattern from one abstract violation scenario. The violation pattern represents multiple abstract violation scenarios, increasing the chance that a corresponding concrete violation exists. Then, we look for a concrete violation that corresponds to the violation pattern by using constraint solving techniques. Finally, we define the class of counterexamples that we can handle and argue correctness of the proposed framework.\ud Our method combines two formal techniques, model checking and constraint solving. Through an analysis of contracting and precise abstractions, we are able to integrate overapproximation by abstraction with concrete counterexample generation