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Sepsis remains a major cause of mortality in intensive care units worldwide, with an estimated 49 million cases and over 11 million deaths annually, highlighting the need for earlier detection to improve outcomes. This systematic review synthesizes evidence on machine learning models for early sepsis prediction in adult ICU patients from 2017 to 2021, focusing on prediction horizons, data modalities, and validation approaches. A comprehensive search of PubMed, Embase, IEEE Xplore, ACM Digital Library, and arXiv identified studies meeting criteria for ICU-based sepsis prediction with at least a 4-hour forecast window, following PRISMA guidelines. Of 1,478 records screened, 35 studies were included, with prediction horizons ranging from 4 to 24 hours and most relying on hourly vital sign data and internal validation. Reported performance varied widely depending on horizon length, data sampling, and validation rigor, with external validation generally producing lower but more realistic results. Overall, while machine learning models show promising predictive ability, limitations in generalizability and standardization remain, emphasizing the need for stronger validation frameworks and reporting practices to support clinical translation.

Sepsis continues to be a major contributor to morbidity and mortality among hospitalized patients globally, especially within intensive care and emergency departments, where rapid recognition is essential for improving survival through timely treatment. In recent years, machine learning approaches have gained attention for their ability to predict sepsis onset using routinely collected electronic health record data. This systematic review, conducted in accordance with PRISMA 2020 guidelines, synthesizes evidence from studies published between 2017 and 2025, focusing on model architectures, feature selection and engineering strategies, prediction time horizons, and validation methodologies. Searches across major biomedical and informatics databases identified 67 eligible studies. The included literature shows that logistic regression, ensemble tree-based algorithms, and deep learning models are most frequently applied for sepsis prediction tasks. However, the majority of studies rely on retrospective datasets with internal validation, while only a limited number incorporate prospective or real-world validation frameworks. Overall, although reported model performance is often strong in retrospective analyses, a consistent decline in accuracy is observed when models are evaluated in real clinical environments. These findings highlight that prospective validation and improved generalizability are still underdeveloped areas, underscoring the need for future research to emphasize real-time deployment and robust external validation before clinical integration.