Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovas...

Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association

Genetic variants that inactivate protein-coding genes are a powerful source of information about the phenotypic consequences of gene disruption: genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation. However, predicted loss-of-function variants are enriched for annotation errors, and tend to be found at extremely low frequencies, so their analysis requires careful variant annotation and very large sample sizes1. Here we describe the aggregation of 125,748 exomes and 15,708 genomes from human sequencing studies into the Genome Aggregation Database (gnomAD). We identify 443,769 high-confidence predicted loss-of-function variants in this cohort after filtering for artefacts caused by sequencing and annotation errors. Using an improved model of human mutation rates, we classify human protein-coding genes along a spectrum that represents tolerance to inactivation, validate this classification using data from model organisms and engineered human cells, and show that it can be used to improve the power of gene discovery for both common and rare diseases. A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

/pdf/the-mutational-constraint-spectrum-quantified-from-variation-2e87wuiyb1.pdf

The mutational constraint spectrum quantified from variation in 141,456 humans

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

Integrative analysis of 111 reference human epigenomes

Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascul...

Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association.

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2-5, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk6. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

/pdf/genome-wide-polygenic-scores-for-common-diseases-identify-477er7o82i.pdf

Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations

We construct a new spectral sequence beginning at the Khovanov homology of a link and converging to the Khovanov homology of the disjoint union of its components. The page at which the sequence collapses gives a lower bound on the splitting number of the link, the minimum number of times its components must be passed through one another in order to completely separate them. In addition, we build on work of Kronheimer-Mrowka and Hedden-Ni to show that Khovanov homology detects the unlink.

A Link Splitting Spectral Sequence in Khovanov Homology

The invention provides a method and apparatus for optimizing code. Embodiments of the present invention comprise, for each expression in an intermediate program representation, transparently forwarding definitions of variables in said expression as said expression is being parsed by a term rewriter, the intermediate program representation being left unchanged; determining whether a term rewriting rule exists in the term rewriter for said expression; and rewriting said expression in the intermediate program representation according to said rule.

Method and apparatus for optimizing code

We construct a new spectral sequence beginning at the Khovanov homology of a link and converging to the Khovanov homology of the disjoint union of its components. The page at which the sequence collapses gives a lower bound on the splitting number of the link, the minimum number of times its components must be passed through one another in order to completely separate them. In addition, we build on work of Kronheimer and Mrowka and Hedden and Ni to show that Khovanov homology detects the unlink.

A link-splitting spectral sequence in Khovanov homology

Autoencoders are a deep learning model for representation learning. When trained to minimize the distance between the data and its reconstruction, linear autoencoders (LAEs) learn the subspace spanned by the top principal directions but cannot learn the principal directions themselves. In this paper, we prove that $L_2$-regularized LAEs are symmetric at all critical points and learn the principal directions as the left singular vectors of the decoder. We smoothly parameterize the critical manifold and relate the minima to the MAP estimate of probabilistic PCA. We illustrate these results empirically and consider implications for PCA algorithms, computational neuroscience, and the algebraic topology of learning.

/pdf/loss-landscapes-of-regularized-linear-autoencoders-3s4o2w7b3v.pdf

Cotton Seed

Papers

A Link Splitting Spectral Sequence in Khovanov Homology

Method and apparatus for optimizing code

A link-splitting spectral sequence in Khovanov homology

Loss Landscapes of Regularized Linear Autoencoders

Curl: a gentle slope language for the Web