AUTHOR=Chen Hang-yu , Li Xiao-xiao , Li Chao , Zhu Hai-chuan , Hou Hong-yan , Zhang Bo , Cheng Li-ming , Hu Hui , Lu Zhong-xin , Liu Jia-xing , Yang Ze-ruo , Zhang Lei , Xu Nuo , Chen Long , He Chuan , Dong Chao-ran , Ge Qing-gang , Lin Jian 

TITLE=5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Early Warning Biomarkers for COVID-19 Progression and Myocardial Injury

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.781267

DOI=10.3389/fcell.2021.781267

ISSN=2296-634X

ABSTRACT=Background  
The symptoms of Coronavirus Disease 2019 (COVID-19) range from moderate to critical conditions leading to death in some patients, the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited. 
Methods
We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5hmC profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and developed a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 with severe COVID-19, and 38 with critical COVID-19. 
Results
Our warning model demonstrated an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95%CI 0.77-0.85), and severe patients developed into critical status was 0.92 (95% CI 0.89-0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95%CI 0.84-0.95). 
Conclusion
This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in COVID-19 patients. Our results show that PDE4D and TET2 may be important markers in the progression of COVID-19 disease.