Towards the Interpretability of Machine Learning Predictions for Medical Applications Targeting Personalised Therapies: A Cancer Case Survey.

Artificial Intelligence is providing astonishing results, with medicine being one of its favourite playgrounds. Machine Learning and, in particular, Deep Neural Networks are behind this revolution. Among the most challenging targets of interest in medicine are cancer diagnosis and therapies but, to start this revolution, software tools need to be adapted to cover the new requirements. In this sense, learning tools are becoming a commodity but, to be able to assist doctors on a daily basis, it is essential to fully understand how models can be interpreted. In this survey, we analyse current machine learning models and other in-silico tools as applied to medicine-specifically, to cancer research-and we discuss their interpretability, performance and the input data they are fed with. Artificial neural networks (ANN), logistic regression (LR) and support vector machines (SVM) have been observed to be the preferred models. In addition, convolutional neural networks (CNNs), supported by the rapid development of graphic processing units (GPUs) and high-performance computing (HPC) infrastructures, are gaining importance when image processing is feasible. However, the interpretability of machine learning predictions so that doctors can understand them, trust them and gain useful insights for the clinical practice is still rarely considered, which is a factor that needs to be improved to enhance doctors' predictive capacity and achieve individualised therapies in the near future.

Machine learning approach to predict medication overuse in migraine patients.

Machine learning (ML) is largely used to develop automatic predictors in migraine classification but automatic predictors for medication overuse (MO) in migraine are still in their infancy. Thus, to understand the benefits of ML in MO prediction, we explored an automated predictor to estimate MO risk in migraine. To achieve this objective, a study was designed to analyze the performance of a customized ML-based decision support system that combines support vector machines and Random Optimization (RO-MO). We used RO-MO to extract prognostic information from demographic, clinical and biochemical data. Using a dataset of 777 consecutive migraine patients we derived a set of predictors with discriminatory power for MO higher than that observed for baseline SVM. The best four were incorporated into the final RO-MO decision support system and risk evaluation on a five-level stratification was performed. ROC analysis resulted in a c-statistic of 0.83 with a sensitivity and specificity of 0.69 and 0.87, respectively, and an accuracy of 0.87 when MO was predicted by at least three RO-MO models. Logistic regression analysis confirmed that the derived RO-MO system could effectively predict MO with ORs of 5.7 and 21.0 for patients classified as probably (3 predictors positive), or definitely at risk of MO (4 predictors positive), respectively. In conclusion, a combination of ML and RO - taking into consideration clinical/biochemical features, drug exposure and lifestyle - might represent a valuable approach to MO prediction in migraine and holds the potential for improving model precision through weighting the relative importance of attributes.

Breast Cancer Prognosis Using a Machine Learning Approach.

Machine learning (ML) has been recently introduced to develop prognostic classification models that can be used to predict outcomes in individual cancer patients. Here, we report the significance of an ML-based decision support system (DSS), combined with random optimization (RO), to extract prognostic information from routinely collected demographic, clinical and biochemical data of breast cancer (BC) patients. A DSS model was developed in a training set (n = 318), whose performance analysis in the testing set (n = 136) resulted in a C-index for progression-free survival of 0.84, with an accuracy of 86%. Furthermore, the model was capable of stratifying the testing set into two groups of patients with low- or high-risk of progression with a hazard ratio (HR) of 10.9 (p < 0.0001). Validation in multicenter prospective studies and appropriate management of privacy issues in relation to digital electronic health records (EHR) data are presently needed. Nonetheless, we may conclude that the implementation of ML algorithms and RO models into EHR data might help to achieve prognostic information, and has the potential to revolutionize the practice of personalized medicine.

Validation of a Machine Learning Approach for Venous Thromboembolism Risk Prediction in Oncology.

Using kernel machine learning (ML) and random optimization (RO) techniques, we recently developed a set of venous thromboembolism (VTE) risk predictors, which could be useful to devise a web interface for VTE risk stratification in chemotherapy-treated cancer patients. This study was designed to validate a model incorporating the two best predictors and to compare their combined performance with that of the currently recommended Khorana score (KS). Age, sex, tumor site/stage, hematological attributes, blood lipids, glycemic indexes, liver and kidney function, BMI, performance status, and supportive and anticancer drugs of 608 cancer outpatients were all entered in the model, with numerical attributes analyzed as continuous values. VTE rate was 7.1%. The VTE risk prediction performance of the combined model resulted in 2.30 positive likelihood ratio (+LR), 0.46 negative LR (-LR), and 4.88 HR (95% CI: 2.54-9.37), with a significant improvement over the KS [HR 1.73 (95% CI: 0.47-6.37)]. These results confirm that a ML approach might be of clinical value for VTE risk stratification in chemotherapy-treated cancer outpatients and suggest that the ML-RO model proposed could be useful to design a web service able to provide physicians with a graphical interface helping in the critical phase of decision making.

Risk Assessment for Venous Thromboembolism in Chemotherapy-Treated Ambulatory Cancer Patients.

OBJECTIVE: To design a precision medicine approach aimed at exploiting significant patterns in data, in order to produce venous thromboembolism (VTE) risk predictors for cancer outpatients that might be of advantage over the currently recommended model (Khorana score). DESIGN: Multiple kernel learning (MKL) based on support vector machines and random optimization (RO) models were used to produce VTE risk predictors (referred to as machine learning [ML]-RO) yielding the best classification performance over a training (3-fold cross-validation) and testing set. RESULTS: Attributes of the patient data set ( n = 1179) were clustered into 9 groups according to clinical significance. Our analysis produced 6 ML-RO models in the training set, which yielded better likelihood ratios (LRs) than baseline models. Of interest, the most significant LRs were observed in 2 ML-RO approaches not including the Khorana score (ML-RO-2: positive likelihood ratio [+LR] = 1.68, negative likelihood ratio [-LR] = 0.24; ML-RO-3: +LR = 1.64, -LR = 0.37). The enhanced performance of ML-RO approaches over the Khorana score was further confirmed by the analysis of the areas under the Precision-Recall curve (AUCPR), and the approaches were superior in the ML-RO approaches (best performances: ML-RO-2: AUCPR = 0.212; ML-RO-3-K: AUCPR = 0.146) compared with the Khorana score (AUCPR = 0.096). Of interest, the best-fitting model was ML-RO-2, in which blood lipids and body mass index/performance status retained the strongest weights, with a weaker association with tumor site/stage and drugs. CONCLUSIONS: Although the monocentric validation of the presented predictors might represent a limitation, these results demonstrate that a model based on MKL and RO may represent a novel methodological approach to derive VTE risk classifiers. Moreover, this study highlights the advantages of optimizing the relative importance of groups of clinical attributes in the selection of VTE risk predictors.