Cell-specific imputation of drug connectivity mapping with incomplete data.

Drug repositioning allows expedited discovery of new applications for existing compounds, but re-screening vast compound libraries is often prohibitively expensive. "Connectivity mapping" is a process that links drugs to diseases by identifying compounds whose impact on expression in a collection of cells reverses the disease's impact on expression in disease-relevant tissues. The LINCS project has expanded the universe of compounds and cells for which data are available, but even with this effort, many clinically useful combinations are missing. To evaluate the possibility of repurposing drugs despite missing data, we compared collaborative filtering using either neighborhood-based or SVD imputation methods to two naive approaches via cross-validation. Methods were evaluated for their ability to predict drug connectivity despite missing data. Predictions improved when cell type was taken into account. Neighborhood collaborative filtering was the most successful method, with the best improvements in non-immortalized primary cells. We also explored which classes of compounds are most and least reliant on cell type for accurate imputation. We conclude that even for cells in which drug responses have not been fully characterized, it is possible to identify unassayed drugs that reverse in those cells the expression signatures observed in disease.

Simple Linear Cancer Risk Prediction Models With Novel Features Outperform Complex Approaches.

PURPOSE: The ability to accurately predict an individual's risk for cancer is critical to the implementation of precision prevention measures. Current cancer risk predictions are frequently made with simple models that use a few proven risk factors, such as the Gail model for breast cancer, which are easy to interpret, but may theoretically be less accurate than advanced machine learning (ML) models. METHODS: With the UK Biobank, a large prospective study, we developed models that predicted 13 cancer diagnoses within a 10-year time span. ML and linear models fit with all features, linear models fit with 10 features, and externally developed QCancer models, which are available to more than 4,000 general practices, were assessed. RESULTS: The average area under the receiver operator curve (AUC) of the linear models (0.722, SE = 0.015) was greater than the average AUC of the ML models (0.720, SE = 0.016) when all 931 features were used. Linear models with only 10 features generated an average AUC of 0.706 (SE 0.015), which was comparable to the complex models using all features and greater than the average AUC of the QCancer models (0.684, SE 0.021). The high performance of the 10-feature linear model may be caused by the consideration of often omitted feature types, including census records and genetic information. CONCLUSION: The high performance of the 10-feature linear models indicate that unbiased selection of diverse features, not ML models, may lead to impressively accurate predictions, possibly enabling personalized screening schedules that increase cancer survival.