Development and multinational validation of an algorithmic strategy for high Lp(a) screening

Area of Science:

• Cardiovascular Medicine
• Artificial Intelligence
• Genetics and Genomics

Background:

• Elevated lipoprotein (a) (Lp(a)) is a significant, heritable risk factor for premature atherosclerotic cardiovascular disease.
• Current Lp(a) testing rates are low (<0.5%), hindering the clinical application of emerging targeted therapies.
• There is a critical need for improved screening strategies to identify individuals at risk due to elevated Lp(a).

Purpose of the Study:

• To develop and validate a machine learning model for targeted screening of elevated Lp(a) (≥150 nmol/L).
• To assess the model's ability to reduce the number of individuals needing testing to identify those with elevated Lp(a).
• To evaluate the model's performance across diverse, large-scale cohort studies.

Main Methods:

• Development of a machine learning model, ARISE (Algorithmic Risk Inspection for Screening Elevated Lp(a)), using data from the UK Biobank (N=456,815).
• External validation of the ARISE model in three independent cohort studies: ARIC (N=14,484), CARDIA (N=4,124), and MESA (N=4,672).
• Analysis of model performance based on reduction in the number needed to test (NNT) to identify individuals with elevated Lp(a).

Main Results:

• The ARISE model demonstrated consistent performance across internal and external validation cohorts.
• ARISE reduced the number needed to test for elevated Lp(a) by up to 67.3%, depending on the probability threshold used.
• The model effectively utilizes commonly available clinical features for screening purposes.

Conclusions:

• The ARISE machine learning model offers a promising tool for optimizing screening for elevated Lp(a).
• Deployment of ARISE in electronic health records could significantly enhance the yield of Lp(a) testing in real-world clinical settings.
• Improved screening facilitated by ARISE may facilitate earlier intervention and better management of cardiovascular risk associated with elevated Lp(a).