Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles.

BACKGROUND: Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. METHODS: While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. RESULTS: Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. CONCLUSIONS: Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

There are various ways in which clinicians can predict the risk of disease progression in patients with leukemia, helping them to treat the patients accordingly. However, these approaches are usually designed by human experts and might not fully capture the complexity of a patient's disease. Here, with a large cohort of patients with acute myeloid leukemia, we design an unsupervised machine learning model ­ a type of computer model that learns from patterns in data without human input­to separate these patients into subgroups according to risk. We identify four distinct groups which differ with regards to patient genetics, laboratory values, and clinical characteristics. These groups have differences in response to treatment and patient survival, and we validate our findings in another dataset. Our approach might help clinicians to better predict outcomes in patients with leukemia and make decisions on treatment.

Prediction of complete remission and survival in acute myeloid leukemia using supervised machine learning.

Achievement of complete remission signifies a crucial milestone in the therapy of acute myeloid leukemia (AML) while refractory disease is associated with dismal outcomes. Hence, accurately identifying patients at risk is essential to tailor treatment concepts individually to disease biology. We used nine machine learning (ML) models to predict complete remission and 2-year overall survival in a large multicenter cohort of 1,383 AML patients who received intensive induction therapy. Clinical, laboratory, cytogenetic and molecular genetic data were incorporated and our results were validated on an external multicenter cohort. Our ML models autonomously selected predictive features including established markers of favorable or adverse risk as well as identifying markers of so-far controversial relevance. De novo AML, extramedullary AML, double-mutated CEBPA, mutations of CEBPA-bZIP, NPM1, FLT3-ITD, ASXL1, RUNX1, SF3B1, IKZF1, TP53, and U2AF1, t(8;21), inv(16)/t(16;16), del(5)/del(5q), del(17)/del(17p), normal or complex karyotypes, age and hemoglobin concentration at initial diagnosis were statistically significant markers predictive of complete remission, while t(8;21), del(5)/del(5q), inv(16)/t(16;16), del(17)/del(17p), double-mutated CEBPA, CEBPA-bZIP, NPM1, FLT3-ITD, DNMT3A, SF3B1, U2AF1, and TP53 mutations, age, white blood cell count, peripheral blast count, serum lactate dehydrogenase level and hemoglobin concentration at initial diagnosis as well as extramedullary manifestations were predictive for 2-year overall survival. For prediction of complete remission and 2-year overall survival areas under the receiver operating characteristic curves ranged between 0.77-0.86 and between 0.63-0.74, respectively in our test set, and between 0.71-0.80 and 0.65-0.75 in the external validation cohort. We demonstrated the feasibility of ML for risk stratification in AML as a model disease for hematologic neoplasms, using a scalable and reusable ML framework. Our study illustrates the clinical applicability of ML as a decision support system in hematology.

Semi-supervised learning in cancer diagnostics.

In cancer diagnostics, a considerable amount of data is acquired during routine work-up. Recently, machine learning has been used to build classifiers that are tasked with cancer detection and aid in clinical decision-making. Most of these classifiers are based on supervised learning (SL) that needs time- and cost-intensive manual labeling of samples by medical experts for model training. Semi-supervised learning (SSL), however, works with only a fraction of labeled data by including unlabeled samples for information abstraction and thus can utilize the vast discrepancy between available labeled data and overall available data in cancer diagnostics. In this review, we provide a comprehensive overview of essential functionalities and assumptions of SSL and survey key studies with regard to cancer care differentiating between image-based and non-image-based applications. We highlight current state-of-the-art models in histopathology, radiology and radiotherapy, as well as genomics. Further, we discuss potential pitfalls in SSL study design such as discrepancies in data distributions and comparison to baseline SL models, and point out future directions for SSL in oncology. We believe well-designed SSL models to strongly contribute to computer-guided diagnostics in malignant disease by overcoming current hinderances in the form of sparse labeled and abundant unlabeled data.

Deep learning identifies Acute Promyelocytic Leukemia in bone marrow smears.

BACKGROUND: Acute promyelocytic leukemia (APL) is considered a hematologic emergency due to high risk of bleeding and fatal hemorrhages being a major cause of death. Despite lower death rates reported from clinical trials, patient registry data suggest an early death rate of 20%, especially for elderly and frail patients. Therefore, reliable diagnosis is required as treatment with differentiation-inducing agents leads to cure in the majority of patients. However, diagnosis commonly relies on cytomorphology and genetic confirmation of the pathognomonic t(15;17). Yet, the latter is more time consuming and in some regions unavailable. METHODS: In recent years, deep learning (DL) has been evaluated for medical image recognition showing outstanding capabilities in analyzing large amounts of image data and provides reliable classification results. We developed a multi-stage DL platform that automatically reads images of bone marrow smears, accurately segments cells, and subsequently predicts APL using image data only. We retrospectively identified 51 APL patients from previous multicenter trials and compared them to 1048 non-APL acute myeloid leukemia (AML) patients and 236 healthy bone marrow donor samples, respectively. RESULTS: Our DL platform segments bone marrow cells with a mean average precision and a mean average recall of both 0.97. Further, it achieves high accuracy in detecting APL by distinguishing between APL and non-APL AML as well as APL and healthy donors with an area under the receiver operating characteristic of 0.8575 and 0.9585, respectively, using visual image data only. CONCLUSIONS: Our study underlines not only the feasibility of DL to detect distinct morphologies that accompany a cytogenetic aberration like t(15;17) in APL, but also shows the capability of DL to abstract information from a small medical data set, i. e. 51 APL patients, and infer correct predictions. This demonstrates the suitability of DL to assist in the diagnosis of rare cancer entities. As our DL platform predicts APL from bone marrow smear images alone, this may be used to diagnose APL in regions were molecular or cytogenetic subtyping is not routinely available and raise attention to suspected cases of APL for expert evaluation.

Deep learning detects acute myeloid leukemia and predicts NPM1 mutation status from bone marrow smears.

The evaluation of bone marrow morphology by experienced hematopathologists is essential in the diagnosis of acute myeloid leukemia (AML); however, it suffers from a lack of standardization and inter-observer variability. Deep learning (DL) can process medical image data and provides data-driven class predictions. Here, we apply a multi-step DL approach to automatically segment cells from bone marrow images, distinguish between AML samples and healthy controls with an area under the receiver operating characteristic (AUROC) of 0.9699, and predict the mutation status of Nucleophosmin 1 (NPM1)-one of the most common mutations in AML-with an AUROC of 0.92 using only image data from bone marrow smears. Utilizing occlusion sensitivity maps, we observed so far unreported morphologic cell features such as a pattern of condensed chromatin and perinuclear lightening zones in myeloblasts of NPM1-mutated AML and prominent nucleoli in wild-type NPM1 AML enabling the DL model to provide accurate class predictions.

Reinforcement Learning for Precision Oncology.

Precision oncology is grounded in the increasing understanding of genetic and molecular mechanisms that underly malignant disease and offer different treatment pathways for the individual patient. The growing complexity of medical data has led to the implementation of machine learning techniques that are vastly applied for risk assessment and outcome prediction using either supervised or unsupervised learning. Still largely overlooked is reinforcement learning (RL) that addresses sequential tasks by exploring the underlying dynamics of an environment and shaping it by taking actions in order to maximize cumulative rewards over time, thereby achieving optimal long-term outcomes. Recent breakthroughs in RL demonstrated remarkable results in gameplay and autonomous driving, often achieving human-like or even superhuman performance. While this type of machine learning holds the potential to become a helpful decision support tool, it comes with a set of distinctive challenges that need to be addressed to ensure applicability, validity and safety. In this review, we highlight recent advances of RL focusing on studies in oncology and point out current challenges and pitfalls that need to be accounted for in future studies in order to successfully develop RL-based decision support systems for precision oncology.

Application of machine learning in the management of acute myeloid leukemia: current practice and future prospects.

Machine learning (ML) is rapidly emerging in several fields of cancer research. ML algorithms can deal with vast amounts of medical data and provide a better understanding of malignant disease. Its ability to process information from different diagnostic modalities and functions to predict prognosis and suggest therapeutic strategies indicates that ML is a promising tool for the future management of hematologic malignancies; acute myeloid leukemia (AML) is a model disease of various recent studies. An integration of these ML techniques into various applications in AML management can assure fast and accurate diagnosis as well as precise risk stratification and optimal therapy. Nevertheless, these techniques come with various pitfalls and need a strict regulatory framework to ensure safe use of ML. This comprehensive review highlights and discusses recent advances in ML techniques in the management of AML as a model disease of hematologic neoplasms, enabling researchers and clinicians alike to critically evaluate this upcoming, potentially practice-changing technology.