Uncovering Clinical Risk Factors and Predicting Severe COVID-19 Cases Using UK Biobank Data: Machine Learning Approach
Authors: Wong Kenneth Chi-Yin , Xiang Yong , Yin Liangying , So Hon-Cheong 
Published: September 2021

Background
COVID-19 is a major public health concern. Given the extent of the pandemic, it is urgent to identify risk factors associated with disease severity. More accurate prediction of those at risk of developing severe infections is of high clinical importance.

Objective
Based on the UK Biobank (UKBB), we aimed to build machine learning models to predict the risk of developing severe or fatal infections, and uncover major risk factors involved.

Methods
We first restricted the analysis to infected individuals (n=7846), then performed analysis at a population level, considering those with no known infection as controls (ncontrols=465,728). Hospitalization was used as a proxy for severity. A total of 97 clinical variables (collected prior to the COVID-19 outbreak) covering demographic variables, comorbidities, blood measurements (eg, hematological/liver/renal function/metabolic parameters), anthropometric measures, and other risk factors (eg, smoking/drinking) were included as predictors. We also constructed a simplified (lite) prediction model using 27 covariates that can be more easily obtained (demographic and comorbidity data). XGboost (gradient-boosted trees) was used for prediction and predictive performance was assessed by cross-validation. Variable importance was quantified by Shapley values (ShapVal), permutation importance (PermImp), and accuracy gain. Shapley dependency and interaction plots were used to evaluate the pattern of relationships between risk factors and outcomes.

Results
A total of 2386 severe and 477 fatal cases were identified. For analyses within infected individuals (n=7846), our prediction model achieved area under the receiving-operating characteristic curve (AUC–ROC) of 0.723 (95% CI 0.711-0.736) and 0.814 (95% CI 0.791-0.838) for severe and fatal infections, respectively. The top 5 contributing factors (sorted by ShapVal) for severity were age, number of drugs taken (cnt_tx), cystatin C (reflecting renal function), waist-to-hip ratio (WHR), and Townsend deprivation index (TDI). For mortality, the top features were age, testosterone, cnt_tx, waist circumference (WC), and red cell distribution width. For analyses involving the whole UKBB population, AUCs for severity and fatality were 0.696 (95% CI 0.684-0.708) and 0.825 (95% CI 0.802-0.848), respectively. The same top 5 risk factors were identified for both outcomes, namely, age, cnt_tx, WC, WHR, and TDI. Apart from the above, age, cystatin C, TDI, and cnt_tx were among the top 10 across all 4 analyses. Other diseases top ranked by ShapVal or PermImp were type 2 diabetes mellitus (T2DM), coronary artery disease, atrial fibrillation, and dementia, among others. For the “lite” models, predictive performances were broadly similar, with estimated AUCs of 0.716, 0.818, 0.696, and 0.830, respectively. The top ranked variables were similar to above, including age, cnt_tx, WC, sex (male), and T2DM.

Conclusions
We identified numerous baseline clinical risk factors for severe/fatal infection by XGboost. For example, age, central obesity, impaired renal function, multiple comorbidities, and cardiometabolic abnormalities may predispose to poorer outcomes. The prediction models may be useful at a population level to identify those susceptible to developing severe/fatal infections, facilitating targeted prevention strategies. A risk-prediction tool is also available online. Further replications in independent cohorts are required to verify our findings.