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

The Naval Postgraduate School secure archival storage system, Part I. Design

There is an increasing need tor systems which Drovide controlled access to multiple levels ot sensitive data and intormaticn. This rencrt comorises the first phase ot the realization ot such a system: the comprehensive design ot a multilevel secure tile storage system. This is the tocus ot an ongoing research oroject, which is currently in the early implementation phases. The design is based uocn security kernel technology as applied to modern multiple microcomputer arrays. This design is intended to interface with other (distributed) Drocessing elements, perhaps torminq the central hub ot a data secure network ot computers. The design would orovide archival shared storage while insuring that each interfacing processor accessed only that information appropriate. The design ohase of the orcject is presented in a series of three research reports (Masters Oegree theses) . These reports, reorinted in their entirety here are: (1) Capt, O'Conneli and Lt. Richardson's definition ot a secure multi-microprocessor family of operating systems; (2) Cant- Coleman's detailed security kernel design tor a member ot this family; and (3) Lt. Parks' hierarchical tile system designed to run under the control ot Capt. Coleman's security kernel.supported in part by the Foundation Research Program of the Naval Postgraduate School with funds provided by the Chief of Naval Researchhttp://archive.org/details/navalpostgraduat00scheNoool480WR00Q5

Performance prediction from a computer hardware description

Today's computers are among the most complex man made systems in existence today. How can we make our designs not only more precise, but make these systems more accurately and cost effectively achieve their goals? We have begun to rely upon computer aided design techniques. The use of these techniques often commences not with the statement of the system goals, but rather with the specification of an architecture and a logic technology. In view of the high costs of computer development, we should be quite confident that our architecture/technology combination is capable of meeting the system requirements before we proceed to more detailed design phases. The entire system design process must be integrated, and include performance prediction and verification techniques. This design process should be reflected in a single description language. A methodology for accomplishing this goal capable of employing many existing design practices is discussed here. (Author)Prepared for: Chief of Naval Research; Arlington, VA 22217. -- Cover.http://archive.org/details/performancepredi00coxlNOOO1480WR0005

The text editor as a uniform man/machine interface : a proposal for a standard editor

There is a substantial group of professionals, scientists, engineers, and managers who are justifiably reluctant to use computer networks such as the ARPANET. This phenomenon continues despite the fact that they recognize some of the benefits of computational assistance, that they have had experience using computer systems, and that they have access to such a network. Their reluctance usually stems from the feeling that the very machines and systems is not justified by the occasional or intermittent nature of their computational problems. In learning to use a new system, a large part of the familiarization effort is spent in trying to learn to use a new text editing program. If such a utility program were standardized and made available on all of the machines on the network, a large obstacle to the efficient use of such systems might be removed. The design of such a system, a Standard Line EDitor called SLED is proposed here. (Author)supported in part by the Foundation Research Program of the Naval Postgraduate Schoolhttp://archive.org/details/texteditorasunif00coxlfunds provided by the Chief of Naval Researc

Resume of Lyle Ashton Cox, Jr, 1978

Naval Postgraduate School Faculty Resum

The Naval Postgraduate School secure archival storage system, Part II : Segment and process management implementation

The security kernel technology has provided the technical foundation for highly reliable protection of computerized information. However, the operating system implementations face two significant challenges: providing (1) adequate computational resources for applications tasks, and (2) a clean, straightforward structure whose correctness can be easily reviewed. This paper presents the experience on an ongoing security kernel implementation using the Advanced Micro Devices 4116 single-board computer based on the Z8002 microprocessor. The performance issues of process switching, domain changing, and multiprocessor bus contention are explicitly addressed. The strictly hierarchical (i.e., loop-free) structure provides a series of increasingly capable, separately usable operating system subsets. Security enforcement is structured in two layers: the basic kernel rigorously enforces a non-discretionary (viz., lattice model) policy, while an upper layer provides the access refinements for a discretionary policy. (Author)supported by grants from the Office of Naval Research, Project No. 427-001, monitored by Mr. Joel Trimble, and the Naval Postgraduate School Research Foundationhttp://archive.org/details/navalpostgraduat00coxlN000148lWRl003

Baseline implementations of the Standard Line Editor (SLED)

In response to a recognized requirement for a more uniform man machine interface, especially in multiple machine networks, a standardized text editor was proposed (1). This editor, "SLED" was designed to be easily implementable in several commonly available higher level languages. This document reviews two baseline implementations taken directly from the SLED standards which users may want to consider when implementing SLED upon local systems. These baseline programs were written and documented with portability and understandabil ity as goals.Prepared for Naval Postgraduate School, Monterey California 93940.http://archive.org/details/baselineimplemen00coxlNaval Postgraduate School, Monterey, CA.NAApproved for public release; distribution is unlimited

Mapping the human genetic architecture of COVID-19

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease