Learning Individual Survival Models from PanCancer Whole Transcriptome Data.

PURPOSE: Personalized medicine attempts to predict survival time for each patient, based on their individual tumor molecular profile. We investigate whether our survival learner in combination with a dimension reduction method can produce useful survival estimates for a variety of patients with cancer. EXPERIMENTAL DESIGN: This article provides a method that learns a model for predicting the survival time for individual patients with cancer from the PanCancer Atlas: given the (16,335 dimensional) gene expression profiles from 10,173 patients, each having one of 33 cancers, this method uses unsupervised nonnegative matrix factorization (NMF) to reexpress the gene expression data for each patient in terms of 100 learned NMF factors. It then feeds these 100 factors into the Multi-Task Logistic Regression (MTLR) learner to produce cancer-specific models for each of 20 cancers (with >50 uncensored instances); this produces "individual survival distributions" (ISD), which provide survival probabilities at each future time for each individual patient, which provides a patient's risk score and estimated survival time. RESULTS: Our NMF-MTLR concordance indices outperformed the VAECox benchmark by 14.9% overall. We achieved optimal survival prediction using pan-cancer NMF in combination with cancer-specific MTLR models. We provide biological interpretation of the NMF model and clinical implications of ISDs for prognosis and therapeutic response prediction. CONCLUSIONS: NMF-MTLR provides many benefits over other models: superior model discrimination, superior calibration, meaningful survival time estimates, and accurate probabilistic estimates of survival over time for each individual patient. We advocate for the adoption of these cancer survival models in clinical and research settings.

Safe opioid prescribing: a prognostic machine learning approach to predicting 30-day risk after an opioid dispensation in Alberta, Canada.

OBJECTIVE: To develop machine learning models employing administrative health data that can estimate risk of adverse outcomes within 30 days of an opioid dispensation for use by health departments or prescription monitoring programmes. DESIGN, SETTING AND PARTICIPANTS: This prognostic study was conducted in Alberta, Canada between 2017 and 2018. Participants included all patients 18 years of age and older who received at least one opioid dispensation. Pregnant and cancer patients were excluded. EXPOSURE: Each opioid dispensation served as an exposure. MAIN OUTCOMES/MEASURES: Opioid-related adverse outcomes were identified from linked administrative health data. Machine learning algorithms were trained using 2017 data to predict risk of hospitalisation, emergency department visit and mortality within 30 days of an opioid dispensation. Two validation sets, using 2017 and 2018 data, were used to evaluate model performance. Model discrimination and calibration performance were assessed for all patients and those at higher risk. Machine learning discrimination was compared with current opioid guidelines. RESULTS: Participants in the 2017 training set (n=275 150) and validation set (n=117 829) had similar baseline characteristics. In the 2017 validation set, c-statistics for the XGBoost, logistic regression and neural network classifiers were 0.87, 0.87 and 0.80, respectively. In the 2018 validation set (n=393 023), the corresponding c-statistics were 0.88, 0.88 and 0.82. C-statistics from the Canadian guidelines ranged from 0.54 to 0.69 while the US guidelines ranged from 0.50 to 0.62. The top five percentile of predicted risk for the XGBoost and logistic regression classifiers captured 42% of all events and translated into post-test probabilities of 13.38% and 13.45%, respectively, up from the pretest probability of 1.6%. CONCLUSION: Machine learning classifiers, especially incorporating hospitalisation/physician claims data, have better predictive performance compared with guideline or prescription history only approaches when predicting 30-day risk of adverse outcomes. Prescription monitoring programmes and health departments with access to administrative data can use machine learning classifiers to effectively identify those at higher risk compared with current guideline-based approaches.

Gene expression based survival prediction for cancer patients-A topic modeling approach.

Cancer is one of the leading cause of death, worldwide. Many believe that genomic data will enable us to better predict the survival time of these patients, which will lead to better, more personalized treatment options and patient care. As standard survival prediction models have a hard time coping with the high-dimensionality of such gene expression data, many projects use some dimensionality reduction techniques to overcome this hurdle. We introduce a novel methodology, inspired by topic modeling from the natural language domain, to derive expressive features from the high-dimensional gene expression data. There, a document is represented as a mixture over a relatively small number of topics, where each topic corresponds to a distribution over the words; here, to accommodate the heterogeneity of a patient's cancer, we represent each patient (≈ document) as a mixture over cancer-topics, where each cancer-topic is a mixture over gene expression values (≈ words). This required some extensions to the standard LDA model-e.g., to accommodate the real-valued expression values-leading to our novel discretized Latent Dirichlet Allocation (dLDA) procedure. After using this dLDA to learn these cancer-topics, we can then express each patient as a distribution over a small number of cancer-topics, then use this low-dimensional "distribution vector" as input to a learning algorithm-here, we ran the recent survival prediction algorithm, MTLR, on this representation of the cancer dataset. We initially focus on the METABRIC dataset, which describes each of n = 1,981 breast cancer patients using the r = 49,576 gene expression values, from microarrays. Our results show that our approach (dLDA followed by MTLR) provides survival estimates that are more accurate than standard models, in terms of the standard Concordance measure. We then validate this "dLDA+MTLR" approach by running it on the n = 883 Pan-kidney (KIPAN) dataset, over r = 15,529 gene expression values-here using the mRNAseq modality-and find that it again achieves excellent results. In both cases, we also show that the resulting model is calibrated, using the recent "D-calibrated" measure. These successes, in two different cancer types and expression modalities, demonstrates the generality, and the effectiveness, of this approach. The dLDA+MTLR source code is available at https://github.com/nitsanluke/GE-LDA-Survival.

A DREAM Challenge to Build Prediction Models for Short-Term Discontinuation of Docetaxel in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: Docetaxel has a demonstrated survival benefit for patients with metastatic castration-resistant prostate cancer (mCRPC); however, 10% to 20% of patients discontinue docetaxel prematurely because of toxicity-induced adverse events, and the management of risk factors for toxicity remains a challenge. PATIENTS AND METHODS: The comparator arms of four phase III clinical trials in first-line mCRPC were collected, annotated, and compiled, with a total of 2,070 patients. Early discontinuation was defined as treatment stoppage within 3 months as a result of adverse treatment effects; 10% of patients discontinued treatment. We designed an open-data, crowd-sourced DREAM Challenge for developing models with which to predict early discontinuation of docetaxel treatment. Clinical features for all four trials and outcomes for three of the four trials were made publicly available, with the outcomes of the fourth trial held back for unbiased model evaluation. Challenge participants from around the world trained models and submitted their predictions. Area under the precision-recall curve was the primary metric used for performance assessment. RESULTS: In total, 34 separate teams submitted predictions. Seven models with statistically similar area under precision-recall curves (Bayes factor ≤ 3) outperformed all other models. A postchallenge analysis of risk prediction using these seven models revealed three patient subgroups: high risk, low risk, or discordant risk. Early discontinuation events were two times higher in the high-risk subgroup compared with the low-risk subgroup. Simulation studies demonstrated that use of patient discontinuation prediction models could reduce patient enrollment in clinical trials without the loss of statistical power. CONCLUSION: This work represents a successful collaboration between 34 international teams that leveraged open clinical trial data. Our results demonstrate that routinely collected clinical features can be used to identify patients with mCRPC who are likely to discontinue treatment because of adverse events and establishes a robust benchmark with implications for clinical trial design.