Integrative COVID-19 biological network inference with probabilistic core decomposition.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of deaths around the world. To help contribute to the understanding of crucial knowledge and to further generate new hypotheses relevant to SARS-CoV-2 and human protein interactions, we make use of the information abundant Biomine probabilistic database and extend the experimentally identified SARS-CoV-2-human protein-protein interaction (PPI) network in silico. We generate an extended network by integrating information from the Biomine database, the PPI network and other experimentally validated results. To generate novel hypotheses, we focus on the high-connectivity sub-communities that overlap most with the integrated experimentally validated results in the extended network. Therefore, we propose a new data analysis pipeline that can efficiently compute core decomposition on the extended network and identify dense subgraphs. We then evaluate the identified dense subgraph and the generated hypotheses in three contexts: literature validation for uncovered virus targeting genes and proteins, gene function enrichment analysis on subgraphs and literature support on drug repurposing for identified tissues and diseases related to COVID-19. The major types of the generated hypotheses are proteins with their encoding genes and we rank them by sorting their connections to the integrated experimentally validated nodes. In addition, we compile a comprehensive list of novel genes, and proteins potentially related to COVID-19, as well as novel diseases which might be comorbidities. Together with the generated hypotheses, our results provide novel knowledge relevant to COVID-19 for further validation.

The impact of lockdown timing on COVID-19 transmission across US counties.

BACKGROUND: Many countries have implemented lockdowns to reduce COVID-19 transmission. However, there is no consensus on the optimal timing of these lockdowns to control community spread of the disease. Here we evaluated the relationship between timing of lockdowns, along with other risk factors, and the growth trajectories of COVID-19 across 3,112 counties in the US. METHODS: We ascertained dates for lockdowns and implementation of various non-pharmaceutical interventions at a county level and merged these data with those of US census and county-specific COVID-19 daily cumulative case counts. We then applied a Functional Principal Component (FPC) analysis on this dataset to generate FPC scores, which were used as a surrogate variable to describe the trajectory of daily cumulative case counts for each county. We used machine learning methods to identify risk factors including the timing of lockdown that significantly influenced the FPC scores. FINDINGS: We found that the first eigen-function accounted for most (>92%) of the variations in the daily cumulative case counts. The impact of lockdown timing on the total daily case count of a county became significant beginning approximately 7 days prior to that county reporting at least 5 cumulative cases of COVID-19. Delays in lockdown implementation after this date led to a rapid acceleration of COVID-19 spread in the county over the first ~50 days from the date with at least 5 cumulative cases, and higher case counts across the entirety of the follow-up period. Other factors such as total population, median family income, Gini index, median age, and within-county mobility also had a substantial effect. When adjusted for all these factors, the timing of lockdowns was the most significant risk factor associated with the county-specific daily cumulative case counts. INTERPRETATION: Lockdowns are an effective way of controlling the spread of COVID-19 in communities. Significant delays in lockdown cause a dramatic increase in the cumulative case counts. Thus, the timing of the lockdown relative to the case count is an important consideration in controlling the pandemic in communities. FUNDING: The study period is from June 2020 to July 2021. Dr. Xuekui Zhang is a Tier 2 Canada Research Chairs (Grant No. 950231363) and funded by Natural Sciences and Engineering Research Council of Canada (Grant No. RGPIN201704722). Dr. Li Xing is funded by Natural Sciences and Engineering Research Council of Canada (Grant Number: RGPIN 202103530). This research was enabled in part by support provided by WestGrid (www.westgrid.ca) and Compute Canada (www.computecanada.ca). The computing resource is provided by Compute Canada Resource Allocation Competitions #3495 (PI: Xuekui Zhang) and #1551 (PI: Li Xing). Dr. Don Sin is a Tier 1 Canada Research Chair in COPD and holds the de Lazzari Family Chair at the Heart Lung Innovation, Vancouver, Canada.