Can machine learning bring cardiovascular risk assessment to the next level? A methodological study using FOURIER trial data.

Aims: Through this proof of concept, we studied the potential added value of machine learning (ML) methods in building cardiovascular risk scores from structured data and the conditions under which they outperform linear statistical models. Methods and results: Relying on extensive cardiovascular clinical data from FOURIER, a randomized clinical trial to test for evolocumab efficacy, we compared linear models, neural networks, random forest, and gradient boosting machines for predicting the risk of major adverse cardiovascular events. To study the relative strengths of each method, we extended the comparison to restricted subsets of the full FOURIER dataset, limiting either the number of available patients or the number of their characteristics. When using all the 428 covariates available in the dataset, ML methods significantly (c-index 0.67, P-value 2e-5) outperformed linear models built from the same variables (c-index 0.62), as well as a reference cardiovascular risk score based on only 10 variables (c-index 0.60). We showed that gradient boosting-the best performing model in our setting-requires fewer patients and significantly outperforms linear models when using large numbers of variables. On the other hand, we illustrate how linear models suffer from being trained on too many variables, thus requiring a more careful prior selection. These ML methods proved to consistently improve risk assessment, to be interpretable despite their complexity and to help identify the minimal set of covariates necessary to achieve top performance. Conclusion: In the field of secondary cardiovascular events prevention, given the increased availability of extensive electronic health records, ML methods could open the door to more powerful tools for patient risk stratification and treatment allocation strategies.

Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen.

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca's large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.