Complete Blood Count and Monocyte Distribution Width–Based Machine Learning Algorithms for Sepsis Detection: Multicentric Development and External Validation Study
Authors: Campagner Andrea , Agnello Luisa , Carobene Anna , Padoan Andrea , Del Ben Fabio , Locatelli Massimo , Plebani Mario , Ognibene Agostino , Lorubbio Maria , De Vecchi Elena , Cortegiani Andrea , Piva Elisa , Poz Donatella , Curcio Francesco , Cabitza Federico , Ciaccio Marcello 
Published: September 2024

Background
Sepsis is an organ dysfunction caused by a dysregulated host response to infection. Early detection is fundamental to improving the patient outcome. Laboratory medicine can play a crucial role by providing biomarkers whose alteration can be detected before the onset of clinical signs and symptoms. In particular, the relevance of monocyte distribution width (MDW) as a sepsis biomarker has emerged in the previous decade. However, despite encouraging results, MDW has poor sensitivity and positive predictive value when compared to other biomarkers.

Objective
This study aims to investigate the use of machine learning (ML) to overcome the limitations mentioned earlier by combining different parameters and therefore improving sepsis detection. However, making ML models function in clinical practice may be problematic, as their performance may suffer when deployed in contexts other than the research environment. In fact, even widely used commercially available models have been demonstrated to generalize poorly in out-of-distribution scenarios.

Methods
In this multicentric study, we developed ML models whose intended use is the early detection of sepsis on the basis of MDW and complete blood count parameters. In total, data from 6 patient cohorts (encompassing 5344 patients) collected at 5 different Italian hospitals were used to train and externally validate ML models. The models were trained on a patient cohort encompassing patients enrolled at the emergency department, and it was externally validated on 5 different cohorts encompassing patients enrolled at both the emergency department and the intensive care unit. The cohorts were selected to exhibit a variety of data distribution shifts compared to the training set, including label, covariate, and missing data shifts, enabling a conservative validation of the developed models. To improve generalizability and robustness to different types of distribution shifts, the developed ML models combine traditional methodologies with advanced techniques inspired by controllable artificial intelligence (AI), namely cautious classification, which gives the ML models the ability to abstain from making predictions, and explainable AI, which provides health operators with useful information about the models’ functioning.

Results
The developed models achieved good performance on the internal validation (area under the receiver operating characteristic curve between 0.91 and 0.98), as well as consistent generalization performance across the external validation datasets (area under the receiver operating characteristic curve between 0.75 and 0.95), outperforming baseline biomarkers and state-of-the-art ML models for sepsis detection. Controllable AI techniques were further able to improve performance and were used to derive an interpretable set of diagnostic rules.

Conclusions
Our findings demonstrate how controllable AI approaches based on complete blood count and MDW may be used for the early detection of sepsis while also demonstrating how the proposed methodology can be used to develop ML models that are more resistant to different types of data distribution shifts.