Deploying unsupervised clustering analysis to derive clinical phenotypes and risk factors associated with mortality risk in 2022 critically ill patients with COVID-19 in Spain

Abstract

Background: The identification of factors associated with Intensive Care Unit (ICU) mortality and derived clinical phenotypes in COVID-19 patients could help for a more tailored approach to clinical decision-making that improves prognostic outcomes.

Methods: Prospective, multicenter, observational study of critically ill patients with confirmed COVID-19 disease and acute respiratory failure admitted from 63 ICUs in Spain. The objective was to utilize an unsupervised clustering analysis to derive clinical COVID-19 phenotypes and to analyze patient's factors associated with mortality risk. Patient features including demographics and clinical data at ICU admission were analyzed. Generalized linear models were used to determine ICU morality risk factors. The prognostic models were validated and their performance was measured using accuracy test, sensitivity, specificity and ROC curves.

Results: The database included a total of 2022 patients (mean age 64 [IQR 5-71] years, 1423 (70.4%) male, median APACHE II score (13 [IQR 10-17]) and SOFA score (5 [IQR 3-7]) points. The ICU mortality rate was 32.6%. Of the 3 derived phenotypes, the A (mild) phenotype (537; 26.7%) included older age (< 65 years), fewer abnormal laboratory values and less development of complications, B (moderate) phenotype (623, 30.8%) had similar characteristics of A phenotype but were more likely to present shock. The C (severe) phenotype was the most common (857; 42.5%) and was characterized by the interplay of older age (> 65 years), high severity of illness and a higher likelihood of development shock. Crude ICU mortality was 20.3%, 25% and 45.4% for A, B and C phenotype respectively. The ICU mortality risk factors and model performance differed between whole population and phenotype classifications.

Conclusion: The presented machine learning model identified three clinical phenotypes that significantly correlated with host-response patterns and ICU mortality. Different risk factors across the whole population and clinical phenotypes were observed which may limit the application of a "one-size-fits-all" model in practice.

Keywords: Machine learning; Phenotypes; Prognosis; Risk factors; Severe SARS-CoV-2 infection.

Fig. 1

Overview of the primary analysis plan. ICU Intensive care units, PAM partition around medoids clustering analysis, GLM Generalized Linear model

Fig. 2

Phenotype clinical characterization (APACHE II Acute Physiology and Chronic Health Evaluation II, SOFA Sequential Organ Failure Assessment, LDH D-Lactate dehydrogenase, U/L, AKI Acute Kidney injury)

Fig. 3

a Chord diagrams showing abnormal clinical variables by phenotype. A: mild COVID-19 disease; B: moderate COVID-19 disease and C: severe COVID-19 disease. b Chord diagrams showing abnormal clinical variables by Phenotype differentiating survivors (green) from non-survivors (red) (APACHE II Acute Physiology and Chronic Health Evaluation II, SOFA Sequential Organ Failure Assessment, PCT Procalcitonin, > 3 chest X-ray more than 3 quadrants infiltrates in the chest X-ray, Miocard Dys Myocardial dysfunction, Hydroxichloroq. Hydroxychloroquine, GAP antiviral Time in days from onset of symptoms to first dose of antiviral, DD D dimer, AKI Acute Kidney injury, LDH D-Lactate dehydrogenase, U/L, COPD Chronic Pulmonary Obstructive Disease, Pa/Fi Partial pressure arterial oxygen/fraction of inspired oxygen, Hemat. Dis Hematologic disease, GAP_UCI Time in days from Hospital to ICU admission, Coronary dis. Coronary disease)

Fig. 4

Variables independently associated with ICU mortality in multivariable analysis (GLM: generalized linear model). Data are show as OR (odds ratio) and 95% Confidence interval (SOFA Sequential organ failure assessment, PCT Procalcitonin, PaO₂/FiO₂ Partial pressure arterial oxygen/fraction of inspired oxygen, Dysf Dysfunction, LDH D-Lactate dehydrogenase, MV Mechanical ventilation, AKI Acute Kidney injury, > 2 infiltrates  > 2 infiltrates in chest-X ray)