Machine learning uncovers blood test patterns subphenotypes at hospital admission discerning increased 30-day ICU mortality rates in COVID-19 elderly patients

Background Elderly patients with COVID-19 are among the most numerous populations being admitted in the ICU due to its high mortality rate and high comorbidity incidence. An early severity risk stratification at hospital admission could help optimize ICU usage towards those more vulnerable and critically ill patients. Methods Of 503 Spanish patients aged>64 years admitted in the ICU between 26 Feb and 02 Nov 2020 in two Spanish hospitals, we included 193 quality-controlled patients. The subphenotyping combined PCA and t-SNE dimensionality reduction methods to maximize non-linear correlation and reduce noise among age and full blood count tests (FBC) at hospital admission, followed by hierarchical clustering. Findings We identified five subphenotypes (Eld-ICU-COV19 clusters) with heterogeneous FBC patterns associated to significantly disparate 30-day ICU mortality rates ranging from 2% in a healthy cluster to 44% in a severe cluster, along three moderate clusters. Interpretations To our knowledge, this is the first study using age and FBC at hospital admission to early stratify the risk of death in ICU at 30 days in elderly patients. Our results provide guidance to comprehend the phenotypic classification and disparate severity patterns among elderly ICU patients with COVID-19, based only on age and FBC, that have the potential to establish target groups for early risk stratification or early triage systems to provide personalized treatments or aid the decision-making during resource allocation process for each target Eld-ICU-COV19 cluster, especially in those circumstances with resource scarcity problem. Funding FONDO SUPERA COVID-19 by CRUE-Santander Bank grant SUBCOVERWD-19. #### Research in context Evidence before this study We searched on PubMed and Google Scholar using the search terms “COVID-19”, “SARS-CoV2”, “phenotypes” for research published between 2020 to 2022, with no language restriction, to detect any published study identifying and characterizing phenotypes among ICU COVID-19 patients. A previous COVID-19 phenotyping study found three phenotypes from hospitalized patients associated with significantly disparate 30-day mortality rates (ranging from 2·5 to 60·7%). However, it seems to become harder to find phenotypes with discriminative mortality rates among ICU COVID-19 patients. For example, we found one study that uncovered two phenotypes from 39 ICU COVID-19 patients based on biomarkers with 39% and 63% mortality rates, but such difference was not statistically significant. We also found another study with more success that uncovered two ICU COVID-19 phenotypes using two different trajectories with somehow disparate 28-day mortality rates of 27% versus 37% (Ventilatory ratio trajectories) and of 25% versus 39% (mechanical power trajectories). Added value of this study To our knowledge, this is the first study that uses age and laboratory results at hospital admission (i.e., before ICU admission) in elderly patients to early stratify, prior ICU admission, the risk of death in ICU at 30 days. We classified 193 patients with COVID-19, based on age and ten Full Blood Count (FBC) tests, into five subphenotypes (one healthy, three moderate, and one severe) that showed significantly disparate 30-day ICU mortality rates from 2% to 44%. Implications of all the available evidence Identifying, from elderly ICU patients with COVID-19 (Eld-ICU-COV19), subphenotypes could spur further investigation to analyze the potential differences in their underlying disease mechanisms, acquire better phenotypical understanding among Eld-ICU-COV19 toward better decision-making in distributing the limited resources (including both logistic and medical) as well as shedding light on tailoring personalized treatment for each specific target subgroup in future medical research and clinical trial. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by FONDO SUPERA COVID-19 by CRUE-Santander Bank grant SUBCOVERWD-19. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics comittee of Universitat Politecnica de Valencia gave ethhical approval for this work. Ethics comittee of Hospital Clinic Universitari de Valencia gave ethhical approval for this work. Ethics comittee of Hospital Universitario 12 de Octubre gave ethhical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in the present study is not publicly available. Any expression of interest must be sent upon reasonable request to the authors. * Eld-ICU-COV19 : Elderly ICU patients with COVID-19 ICU : Intensive Care Unit WBC : White Blood Cell RBC : Red Blood Cell OR : Odds Ratio CI : Confidence Interval FBC : Full Blood Count PCA : Principal Component Analysis t-SNE : t-distributed Stochastic Neighbor Embedding