Pattern Recognition Analysis of MR Spectra

The need for multivariate analysis of magnetic resonance spectroscopy (MRS) data was recognized about 20 years ago, when it became evident that spectral patterns were characteristic of some diseases. Despite this, there is no generally accepted methodology for performing pattern recognition (PR) analysis of MRS data sets. Here, the data acquisition and processing requirements for performing successful PR as applied to human MRS studies are introduced, and the main techniques for feature selection, extraction, and classification are described. These include methods of dimensionality reduction such as principal component analysis (PCA), independent component analysis (ICA), non-negative matrix factorization (NMF), and feature selection. Supervised methods such as linear discriminant analysis (LDA), logistic regression (LogR), and nonlinear classification are discussed separately from unsupervised and semisupervised classification techniques, including k –means clustering. Methods for testing and metrics for gauging the performance of PR models (sensitivity and specificity, the ‘Confusion Matrix’, ‘k –fold cross-validation’, ‘Leave One Out’, ‘Bootstrapping’, the ‘Receiver Operating Characteristic curve’, and balanced error and accuracy rates) are briefly described. This article ends with a summary of the main lessons learned from PR applied to MRS to date

Automatic relevance source determination in human brain tumors using Bayesian NMF.

The clinical management of brain tumors is very sensitive; thus, their non-invasive characterization is often preferred. Non-negative Matrix Factorization techniques have been successfully applied in the context of neuro-oncology to extract the underlying source signals that explain different tissue tumor types, for which knowing the number of sources to calculate was always required. In the current study we estimate the number of relevant sources for a set of discrimination problems involving brain tumors and normal brain. For this, we propose to start by calculating a high number of sources using Bayesian NMF and automatically discarding the irrelevant ones during the iterative process of matrices decomposition, hence obtaining a reduced range of interpretable solutions. The real data used in this study come from a widely tested human brain tumor database. Simulated data that resembled the real data was also generated to validate the hypothesis against ground truth. The results obtained suggest that the proposed approach is able to provide a small range of meaningful solutions to the problem of source extraction in human brain tumors

A machine learning pipeline for supporting differentiation of glioblastomas from single brain metastases

Machine learning has provided, over the last decades, tools for knowledge extraction in complex medical domains. Most of these tools, though, are ad hoc solutions and lack the systematic approach that would be required to become mainstream in medical practice. In this brief paper, we define a machine learning-based analysis pipeline for helping in a difficult problem in the field of neuro-oncology, namely the discrimination of brain glioblastomas from single brain metastases. This pipeline involves source extraction using k-Meansinitialized Convex Non-negative Matrix Factorization and a collection of classifiers, including Logistic Regression, Linear Discriminant Analysis, AdaBoost, and Random Forests.Peer ReviewedPostprint (published version

The INTERPRET Decision-Support System version 3.0 for evaluation of Magnetic Resonance Spectroscopy data from human brain tumours and other abnormal brain masses.

Background Proton Magnetic Resonance (MR) Spectroscopy (MRS) is a widely available technique for those clinical centres equipped with MR scanners. Unlike the rest of MR-based techniques, MRS yields not images but spectra of metabolites in the tissues. In pathological situations, the MRS profile changes and this has been particularly described for brain tumours. However, radiologists are frequently not familiar to the interpretation of MRS data and for this reason, the usefulness of decision-support systems (DSS) in MRS data analysis has been explored. Results This work presents the INTERPRET DSS version 3.0, analysing the improvements made from its first release in 2002. Version 3.0 is aimed to be a program that 1st, can be easily used with any new case from any MR scanner manufacturer and 2nd, improves the initial analysis capabilities of the first version. The main improvements are an embedded database, user accounts, more diagnostic discrimination capabilities and the possibility to analyse data acquired under additional data acquisition conditions. Other improvements include a customisable graphical user interface (GUI). Most diagnostic problems included have been addressed through a pattern-recognition based approach, in which classifiers based on linear discriminant analysis (LDA) were trained and tested. Conclusions The INTERPRET DSS 3.0 allows radiologists, medical physicists, biochemists or, generally speaking, any person with a minimum knowledge of what an MR spectrum is, to enter their own SV raw data, acquired at 1.5 T, and to analyse them. The system is expected to help in the categorisation of MR Spectra from abnormal brain masses

Semi-supervised source extraction methodology for the nosological imaging of glioblastoma response to therapy.

Glioblastomas are one the most aggressive brain tumors. Their usual bad prognosis is due to the heterogeneity of their response to treatment and the lack of early and robust biomarkers to decide whether the tumor is responding to therapy. In this work, we propose the use of a semi-supervised methodology for source extraction to identify the sources representing tumor response to therapy, untreated/unresponsive tumor, and normal brain; and create nosological images of the response to therapy based on those sources. Fourteen mice were used to calculate the sources, and an independent test set of eight mice was used to further evaluate the proposed approach. The preliminary results obtained indicate that was possible to discriminate response and untreated/unresponsive areas of the tumor, and that the color-coded images allowed convenient tracking of response, especially throughout the course of therapy

Robust Conditional Independence maps of single-voxel Magnetic Resonance Spectra to elucidate associations between brain tumours and metabolites.

The aim of the paper is two-fold. First, we show that structure finding with the PC algorithm can be inherently unstable and requires further operational constraints in order to consistently obtain models that are faithful to the data. We propose a methodology to stabilise the structure finding process, minimising both false positive and false negative error rates. This is demonstrated with synthetic data. Second, to apply the proposed structure finding methodology to a data set comprising single-voxel Magnetic Resonance Spectra of normal brain and three classes of brain tumours, to elucidate the associations between brain tumour types and a range of observed metabolites that are known to be relevant for their characterisation. The data set is bootstrapped in order to maximise the robustness of feature selection for nominated target variables. Specifically, Conditional Independence maps (CI-maps) built from the data and their derived Bayesian networks have been used. A Directed Acyclic Graph (DAG) is built from CI-maps, being a major challenge the minimization of errors in the graph structure. This work presents empirical evidence on how to reduce false positive errors via the False Discovery Rate, and how to identify appropriate parameter settings to improve the False Negative Reduction. In addition, several node ordering policies are investigated that transform the graph into a DAG. The obtained results show that ordering nodes by strength of mutual information can recover a representative DAG in a reasonable time, although a more accurate graph can be recovered using a random order of samples at the expense of increasing the computation time

A machine learning pipeline for supporting differentiation of glioblastomas from single brain metastases

Machine learning has provided, over the last decades, tools for knowledge extraction in complex medical domains. Most of these tools, though, are ad hoc solutions and lack the systematic approach that would be required to become mainstream in medical practice. In this brief paper, we define a machine learning-based analysis pipeline for helping in a difficult problem in the field of neuro-oncology, namely the discrimination of brain glioblastomas from single brain metastases. This pipeline involves source extraction using k-Meansinitialized Convex Non-negative Matrix Factorization and a collection of classifiers, including Logistic Regression, Linear Discriminant Analysis, AdaBoost, and Random Forests

A Novel Semi-Supervised Methodology for Extracting Tumor Type-Specific MRS Sources in Human Brain Data

BackgroundThe clinical investigation of human brain tumors often starts with a non-invasive imaging study, providing information about the tumor extent and location, but little insight into the biochemistry of the analyzed tissue. Magnetic Resonance Spectroscopy can complement imaging by supplying a metabolic fingerprint of the tissue. This study analyzes single-voxel magnetic resonance spectra, which represent signal information in the frequency domain. Given that a single voxel may contain a heterogeneous mix of tissues, signal source identification is a relevant challenge for the problem of tumor type classification from the spectroscopic signal.Methodology/Principal FindingsNon-negative matrix factorization techniques have recently shown their potential for the identification of meaningful sources from brain tissue spectroscopy data. In this study, we use a convex variant of these methods that is capable of handling negatively-valued data and generating sources that can be interpreted as tumor class prototypes. A novel approach to convex non-negative matrix factorization is proposed, in which prior knowledge about class information is utilized in model optimization. Class-specific information is integrated into this semi-supervised process by setting the metric of a latent variable space where the matrix factorization is carried out. The reported experimental study comprises 196 cases from different tumor types drawn from two international, multi-center databases. The results indicate that the proposed approach outperforms a purely unsupervised process by achieving near perfect correlation of the extracted sources with the mean spectra of the tumor types. It also improves tissue type classification.Conclusions/SignificanceWe show that source extraction by unsupervised matrix factorization benefits from the integration of the available class information, so operating in a semi-supervised learning manner, for discriminative source identification and brain tumor labeling from single-voxel spectroscopy data. We are confident that the proposed methodology has wider applicability for biomedical signal processing

Anti-tumour immune response in GL261 glioblastoma generated by Temozolamide Immune-Enhancing Metronomic Schedule monitored with MRSI-based nosological images

Glioblastomas (GB) are brain tumours with poor prognosis even after aggressive therapy. Improvements in both therapeutic and follow-up strategies are urgently needed. In previous work we described an oscillatory pattern of response to Temozolomide (TMZ) using a standard administration protocol, detected through MRSI-based machine learning approaches. In the present work, we have introduced the Immune-Enhancing Metronomic Schedule (IMS) with an every 6-days TMZ administration at 60mg/kg, and investigated the consistence of such oscillatory behaviour. A total of n=17 GL261 GB tumour-bearing C57BL/6j mice were studied with MRI/MRSI every 2 days, and the oscillatory behaviour (6.2±1.5 days period from the TMZ administration day) was confirmed during response. Furthermore, IMS-TMZ produced significant improvement in mice survival (22.5±3.0 days for controls vs 135.8±78.2 for TMZ-treated), outperforming standard TMZ treatment. Histopathological correlation was investigated in selected tumour samples (n=6) analyzing control and responding fields. Significant differences were found for CD3+ cells (lymphocytes, 3.3±2.5 vs 4.8±2.9 respectively) and Iba-1 immunostained area (microglia/macrophages, 16.8±9.7% and 21.9±11.4% respectively). Unexpectedly, during IMS-TMZ treatment, tumours from some mice (n=6) fully regressed and remained undetectable without further treatment for one month. These animals were considered “cured” and a GL261 re-challenge experiment performed, with no tumour reappearance in 5 out of 6 cases. Heterogeneous therapy response outcomes were detected in tumour-bearing mice, and a selected group was investigated (n=3 non-responders, n=6 relapsing tumours, n=3 controls). PD-L1 content was found ca. 3-fold increased in the relapsing group when comparing with control and non-responding groups, suggesting that increased lymphocyte inhibition could be associated to IMS-TMZ failure. Overall, data suggest that host immune response has a relevant paper in therapy response/escape in GL261 tumours under IMS-TMZ therapy. This is associated to changes in the metabolomics pattern, oscillating every 6 days, in agreement with immune cycle length, which is being sampled by MRSI-derived nosological images

Randomized pilot study and qualitative evaluation of a clinical decision support system for brain tumour diagnosis based on SV 1H MRS: Evaluation as an additional information procedure for novice radiologists

The results of a randomized pilot study and qualitative evaluation of the clinical decision support system Curiam BT are reported. We evaluated the system's feasibility and potential value as a radiological information procedure complementary to magnetic resonance (MR) imaging to assist novice radiologists in diagnosing brain tumours using MR spectroscopy (1.5 and 3.0T). Fifty-five cases were analysed at three hospitals according to four non-exclusive diagnostic questions. Our results show that Curiam BT improved the diagnostic accuracy in all the four questions. Additionally, we discuss the findings of the users' feedback about the system, and the further work to optimize it for real environments and to conduct a large clinical trial. & 2013 Elsevier Ltd. All rights reserved.This work has been supported by the Spanish Ministry of Science and Innovation - Institut de Salud Carlos III - FIS Contract PI09/90177; and Universitat Politecnica de Valencia - INNOVA UPV 2008 2 1834. We specially thank Miguel Angel Edo, Maria Vano, Carmen Barber, Ana Catala-Gregori, Enrique Molla and Cecilio Poyatos, for their collaboration in the development of this study.Sáez Silvestre, C.; Martí-Bonmatí, L.; Alberich Bayarri, Á.; Robles Viejo, M.; García Gómez, JM. (2014). Randomized pilot study and qualitative evaluation of a clinical decision support system for brain tumour diagnosis based on SV 1H MRS: Evaluation as an additional information procedure for novice radiologists. Computers in Biology and Medicine. 45:26-33. https://doi.org/10.1016/j.compbiomed.2013.11.009S26334