Introduction Propofol is a widely used sedative-hypnotic agent for critically-ill patients requiring invasive mechanical ventilation (IMV). Despite its clinical benefits, propofol is associated with increased risks of hypertriglyceridemia. Early identification of patients at risk for propofol-associated hypertriglyceridemia is crucial for optimizing sedation strategies and preventing adverse outcomes. Machine learning (ML) models offer a promising approach to predict individualized patient risks of propofol-associated hypertriglyceridemia. Methods and analysis We propose the development of a ML model aimed at predicting the risk of propofol-associated hypertriglyceridemia in ICU patients receiving IMV. The study will utilize retrospective data from four Mayo Clinic sites. Nested cross-validation (CV) will be employed, with a 10-fold inner CV loop for model tuning and selection as well as an outer loop using leave-one-site-out CV for external validation. Feature selection will be conducted using Boruta and LASSO-penalized logistic regression. Data preprocessing steps include missing data imputation, feature scaling, and dimensionality reduction techniques. Six ML algorithms will be tuned and evaluated. Bayesian optimization will be used for hyperparameter selection. Global model explainability will be assessed using permutation importance, and local model explainability will be assessed using SHAP. Ethics and dissemination The proposed ML model aims to provide a reliable and interpretable tool for clinicians to predict the risk of propofol-associated hypertriglyceridemia in ICU patients. The final model will be deployed in a web-based clinical risk calculator. The model development process and performance measures obtained during nested cross-validation will be described in a study publication to be disseminated in a peer-reviewed journal. The proposed study has received ethics approval from the Mayo Clinic Institutional Review Board (IRB #23-007416).

Jiawen Deng is a member of the OpenAI Researcher Access Program and receives grants in the form of API credits for purposes of research involving large language models from OpenAI. Kiyan Heybati and Hemang Yadav report no relevant conflicts of interest.

This work is supported by the Mayo Clinic Critical Care Research Committee, as well as the National Heart, Lung, and Blood Institute (NHLBI) of the National Institute of Health (NIH) Grant Number K23HL151671 (Recipient: Hemang Yadav). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The proposed study has received ethics approval from the Mayo Clinic Institutional Review Board (IRB #23-007416). The requirement for informed consent is waived by institutional review.

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