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

Prevention of colorectal cancer by combining early detection and chemoprevention

Colorectal cancer is a major cause of cancer-related mortality. Most colorectal cancers arise in precursor lesions over a number of years. The carcinogenetic pathway is modulated by a wide array of genetic and epigenetic factors. Two major approaches to halting carcinogenesis are chemoprevention and early detection. Chemoprevention is an attractive emerging option-advances in understanding the carcinogenetic pathways and progress in evaluating various putative agents are promising. However, several issues regarding efficacy, safety, and acceptability require answers before an ideal agent can come into widespread use. Early detection and removal of precursor lesions show promise in reducing disease burden. Although the concept has been around and has been widely advocated for several years, participation in screening remains low. The ideal test in terms of practicality, accuracy, and safety is still debated. This article reviews the recent literature related to screening and chemoprevention of colorectal cancer. Copyright © 2009 by Current Medicine Group LLC

Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability

Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p lt .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3–9; median total sample = 1,279.5, range = 276–3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Δr =.002 or.014, depending on analytic approach). The median effect size for the revised protocols (r =.05) was similar to that of the RP:P protocols (r =.04) and the original RP:P replications (r =.11), and smaller than that of the original studies (r =.37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r =.07, range =.00–.15) were 78% smaller, on average, than the original effect sizes (median r =.37, range =.19–.50)