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Comparison of unsupervised machine-learning methods to identify metabolomic signatures in patients with localized breast cancer.

ABSTRACT: Genomics and transcriptomics have led to the widely-used molecular classification of breast cancer (BC). However, heterogeneous biological behaviors persist within breast cancer subtypes. Metabolomics is a rapidly-expanding field of study dedicated to cellular metabolisms affected by the environment. The aim of this study was to compare metabolomic signatures of BC obtained by 5 different unsupervised machine learning (ML) methods. Fifty-two consecutive patients with BC with an indication for adjuvant chemotherapy between 2013 and 2016 were retrospectively included. We performed metabolomic profiling of tumor resection samples using liquid chromatography-mass spectrometry. Here, four hundred and forty-nine identified metabolites were selected for further analysis. Clusters obtained using 5 unsupervised ML methods (PCA k-means, sparse k-means, spectral clustering, SIMLR and k-sparse) were compared in terms of clinical and biological characteristics. With an optimal partitioning parameter k = 3, the five methods identified three prognosis groups of patients (favorable, intermediate, unfavorable) with different clinical and biological profiles. SIMLR and K-sparse methods were the most effective techniques in terms of clustering. In-silico survival analysis revealed a significant difference for 5-year predicted OS between the 3 clusters. Further pathway analysis using the 449 selected metabolites showed significant differences in amino acid and glucose metabolism between BC histologic subtypes. Our results provide proof-of-concept for the use of unsupervised ML metabolomics enabling stratification and personalized management of BC patients. The design of novel computational methods incorporating ML and bioinformatics techniques should make available tools particularly suited to improving the outcome of cancer treatment and reducing cancer-related mortalities.

SUBMITTER: Gal J

PROVIDER: S-EPMC7327012 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:BackgroundMutation processes leave different signatures in genes. For single-base substitutions, previous studies have suggested that mutation signatures are not only reflected in mutation bases but also in neighboring bases. However, because of the lack of a method to identify features of long sequences next to mutation bases, the understanding of how flanking sequences influence mutation signatures is limited.MethodsWe constructed a long short-term memory-self organizing map (LSTM-SOM) unsupervised neural network. By extracting mutated sequence features via LSTM and clustering similar features with the SOM, single-base substitutions in The Cancer Genome Atlas database were clustered according to both their mutation site and flanking sequences. The relationship between mutation sequence signatures and clinical features was then analyzed. Finally, we clustered patients into different classes according to the composition of the mutation sequence signatures by the K-means method and then studied the differences in clinical features and survival between classes.ResultsTen classes of mutant sequence signatures (mutation blots, MBs) were obtained from 2,141,527 single-base substitutions via LSTM-SOM machine learning approach. Different features in mutation bases and flanking sequences were revealed among MBs. MBs reflect both the site and pathological features of cancers. MBs were related to clinical features, including age, sex, and cancer stage. The class of an MB in a given gene was associated with survival. Finally, patients were clustered into 7 classes according to the MB composition. Significant differences in survival and clinical features were observed among different patient classes.ConclusionsWe provided a method for analyzing the characteristics of mutant sequences. Result of this study showed that flanking sequences, together with mutation bases, shape the signatures of SBSs. MBs were shown related to clinical features and survival of cancer patients. Composition of MBs is a feasible predictive factor of clinical prognosis. Further study of the mechanism of MBs related to cancer characteristics is suggested.

Project description:BackgroundDementia is increasing in prevalence worldwide, yet frequently remains undiagnosed, especially in low- and middle-income countries. Population-based surveys represent an underinvestigated source to identify individuals at risk of dementia.ObjectiveThe aim is to identify participants with high likelihood of dementia in population-based surveys without the need of the clinical diagnosis of dementia in a subsample.MethodsUnsupervised machine learning classification (hierarchical clustering on principal components) was developed in the Health and Retirement Study (HRS; 2002-2003, N=18,165 individuals) and validated in the Survey of Health, Ageing and Retirement in Europe (SHARE; 2010-2012, N=58,202 individuals).ResultsUnsupervised machine learning classification identified three clusters in HRS: cluster 1 (n=12,231) without any functional or motor limitations, cluster 2 (N=4841) with walking/climbing limitations, and cluster 3 (N=1093) with both functional and walking/climbing limitations. Comparison of cluster 3 with previously published predicted probabilities of dementia in HRS showed that it identified high likelihood of dementia (probability of dementia >0.95; area under the curve [AUC]=0.91). Removing either cognitive or both cognitive and behavioral measures did not impede accurate classification (AUC=0.91 and AUC=0.90, respectively). Three clusters with similar profiles were identified in SHARE (cluster 1: n=40,223; cluster 2: n=15,644; cluster 3: n=2335). Survival rate of participants from cluster 3 reached 39.2% (n=665 deceased) in HRS and 62.2% (n=811 deceased) in SHARE after a 3.9-year follow-up. Surviving participants from cluster 3 in both cohorts worsened their functional and mobility performance over the same period.ConclusionsUnsupervised machine learning identifies high likelihood of dementia in population-based surveys, even without cognitive and behavioral measures and without the need of clinical diagnosis of dementia in a subsample of the population. This method could be used to tackle the global challenge of dementia.

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Comparison of unsupervised machine-learning methods to identify metabolomic signatures in patients with localized breast cancer.

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