Victor Lavrenko

Infections with SARS-CoV-2 and influenza are associated with acute and post-acute complications and sequelae of many organ systems (i.e., disease burden). It is important to understand the global disease burden that associates with and follows acute infection in order to establish preventive and therapeutic strategies and to reduce the use of health resources and improve patient health outcomes. To address these questions, we utilized the National Covid Cohort Collaborative, which is an integrated and harmonized data repository of electronic health record data in the USA. From this database, we included in analysis 346,648 eligible SARS-CoV-2-infected patients, 78,086 eligible influenza infected patients, and 146,635 uninfected controls. We describe the disease burden that extends over 2-3 months following infection, and we quantify the reduction of disease burden by treatment. We identify a burden of disease following medically attended influenza that is comparable to that of medically attended SARS-CoV-2 infection. However, in contrast to SARS-CoV-2, influenza acute infection and disease burden are not responsive to antiviral treatment and thus remain as an unmet medical need. Focusing therapeutic strategies solely on the short-term management of acute infection may also underestimate the extended health benefits of antiviral treatment.

Significance: Advances in technology are enabling evaluation for prevention and early detection of age-related chronic diseases associated with premature mortality, such as cancer and cardiovascular diseases. These diseases kill about one-third of men and one-quarter of women between the ages of 50 and 74 years old in the United States. We used whole-genome sequencing, advanced imaging, and other clinical testing to screen 209 active, symptom-free adults. We identified a broad set of complementary age-related chronic disease risks associated with premature mortality.

Understanding the significance of genetic variants in the noncoding genome is emerging as the next challenge in human genomics. We used the power of 11,257 whole-genome sequences and 16,384 heptamers (7-nt motifs) to build a map of sequence constraint for the human species. This build differed substantially from traditional maps of interspecies conservation and identified regulatory elements among the most constrained regions of the genome. Using new Hi-C experimental data, we describe a strong pattern of coordination over 2 Mb where the most constrained regulatory elements associate with the most essential genes. Constrained regions of the noncoding genome are up to 52-fold enriched for known pathogenic variants as compared to unconstrained regions (21-fold when compared to the genome average). This map of sequence constraint across thousands of individuals is an asset to help interpret noncoding elements in the human genome, prioritize variants and reconsider gene units at a larger scale.

Significance: By associating deidentified genomic data with phenotypic measurements of the contributor, this work challenges current conceptions of genomic privacy. It has significant ethical and legal implications on personal privacy, the adequacy of informed consent, the viability and value of deidentification of data, the potential for police profiling, and more. We invite commentary and deliberation on the implications of these findings for research in genomics, investigatory practices, and the broader legal and ethical implications for society. Although some scholars and commentators have addressed the implications of DNA phenotyping, this work suggests that a deeper analysis is warranted.