Biomarker identification using dynamic time warping analysis: a longitudinal cohort study of patients with COVID-19 in a UK tertiary hospital

Abstract

Objectives: COVID-19 is a heterogeneous disease, and many reports have described variations in demographic, biochemical and clinical features at presentation influencing overall hospital mortality. However, there is little information regarding longitudinal changes in laboratory prognostic variables in relation to disease progression in hospitalised patients with COVID-19.

Design and setting: This retrospective observational report describes disease progression from symptom onset, to admission to hospital, clinical response and discharge/death among patients with COVID-19 at a tertiary centre in South East England.

Participants: Six hundred and fifty-one patients treated for SARS-CoV-2 between March and September 2020 were included in this analysis. Ethical approval was obtained from the HRA Specific Review Board (REC 20/HRA/2986) for waiver of informed consent.

Results: The majority of patients presented within 1 week of symptom onset. The lowest risk patients had low mortality (1/45, 2%), and most were discharged within 1 week after admission (30/45, 67%). The highest risk patients, as determined by the 4C mortality score predictor, had high mortality (27/29, 93%), with most dying within 1 week after admission (22/29, 76%). Consistent with previous reports, most patients presented with high levels of C reactive protein (CRP) (67% of patients >50 mg/L), D-dimer (98%>upper limit of normal (ULN)), ferritin (65%>ULN), lactate dehydrogenase (90%>ULN) and low lymphocyte counts (81%<lower limit of normal (LLN)). Increases in platelet counts and decreases in CRP, neutrophil:lymphocyte ratio (p<0.001), lactate dehydrogenase, neutrophil counts, urea and white cell counts (all p<0.01) were each associated with discharge.

Conclusions: Serial measurement of routine blood tests may be a useful prognostic tool for monitoring treatment response in hospitalised patients with COVID-19. Changes in other biochemical parameters often included in a 'COVID-19 bundle' did not show significant association with outcome, suggesting there may be limited clinical benefit of serial sampling. This may have direct clinical utility in the context of escalating healthcare costs of the pandemic.

Keywords: COVID-19; respiratory infections; respiratory medicine (see thoracic medicine).

Figure 1

Performance of weighted risk score at admission as predictor of mortality. Red bars: predicted mortality based on a univariate logistic regression model of mortality according to weighted risk score at admission. Blue bars: actual observed mortality rate for a given risk score at admission.

Figure 2

Time from admission to outcome according to risk group at admission. Patients were grouped based on weighted risk scores at admission: low (0–3), intermediate, high and very high (>14). Risk scores at admission could not be calculated for some patients due to one or more missing features (‘data missing’ group).

Figure 3

Changes in biochemical parameters between admission and last available specimen. Green line: increase; red line: decrease of parameter value for each individual patient. Biochemical parameters measured at admission were compared with the last available records using Wilcoxon signed-rank test within groups stratified by outcome.

Figure 4

Clustered trajectories of parameter values over the first 7 days after admission: trajectories of biochemical parameters were clustered using the k-means clustering algorithm together with dynamic time warping used as a distance metric, pragmatically setting the number of cluster k=4: (A) CRP; (B) urea; (C) platelet counts; (D) LDH; (E) neutrophil counts; (F) white cell counts; and (G) ymphocyte counts. Each line represents an individual patient: blue: discharged; red: died; black dashed line is a centre of the cluster and green area is normal range. Note: clustering was performed for each parameter separately, that is, CRP cluster #1 does not contain the same patients as urea cluster #1. CRP, C reactive protein; LDH, lactate dehydrogenase.