PLUS: Predicting cancer metastasis potential based on positive and unlabeled learning

Author summaryMetastasis is the major cause of cancer-related deaths, and evaluations of metastasis risk are essential for tailored treatment of cancer patients. Existing methods often build a classifier using the clinical metastasis diagnoses as binary responses or detect genomic features significantly associated with metastasis-related survival outcomes. However, these methods tend to identify genomic predictors that have little consistency across different cancer types. Thus, there is an urgent need for a powerful tool to characterize the cancer metastasis potential applicable across a wide span of cancer types. Computational assessment of metastasis potential based on large-scale transcriptomic cancer data is challenging because metastasis events are not always clinically detectable, which results in biased estimations of metastasis potential. Our proposed algorithm, called PLUS, considers patients with metastasis diagnosis as positive instances and the remainder as unlabeled instances, meaning they are either metastatic or non-metastatic. Such a classifier given by PLUS rendered concordance between the predicted cancer metastasis and observed metastasis survival outcomes in the follow-up data for almost all cancer types considered. The selected genes were found to perform functions consistent with experimental research findings and are capable of clustering the single cells based on their levels of metastasis potential. Metastatic cancer accounts for over 90% of all cancer deaths, and evaluations of metastasis potential are vital for minimizing the metastasis-associated mortality and achieving optimal clinical decision-making. Computational assessment of metastasis potential based on large-scale transcriptomic cancer data is challenging because metastasis events are not always clinically detectable. The under-diagnosis of metastasis events results in biased classification labels, and classification tools using biased labels may lead to inaccurate estimations of metastasis potential. This issue is further complicated by the unknown metastasis prevalence at the population level, the small number of confirmed metastasis cases, and the high dimensionality of the candidate molecular features. Our proposed algorithm, called Positive and unlabeled Learning from Unbalanced cases and Sparse structures (PLUS), is the first to use a positive and unlabeled learning framework to account for the under-detection of metastasis events in building a classifier. PLUS is specifically tailored for studying metastasis that deals with the unbalanced instance allocation as well as unknown metastasis prevalence, which are not considered by other methods. PLUS achieves superior performance on synthetic datasets compared with other state-of-the-art methods. Application of PLUS to The Cancer Genome Atlas Pan-Cancer gene expression data generated metastasis potential predictions that show good agreement with the clinical follow-up data, in addition to predictive genes that have been validated by independent single-cell RNA-sequencing datasets.