k-strip: A novel segmentation algorithm in k-space for the application of skull stripping

Objectives: Present a novel deep learning-based skull stripping algorithm for magnetic resonance imaging (MRI) that works directly in the information rich k-space. Materials and Methods: Using two datasets from different institutions with a total of 36,900 MRI slices, we trained a deep learning-based model to work directly with the complex raw k-space data. Skull stripping performed by HD-BET (Brain Extraction Tool) in the image domain were used as the ground truth. Results: Both datasets were very similar to the ground truth (DICE scores of 92\%-98\% and Hausdorff distances of under 5.5 mm). Results on slices above the eye-region reach DICE scores of up to 99\%, while the accuracy drops in regions around the eyes and below, with partially blurred output. The output of k-strip often smoothed edges at the demarcation to the skull. Binary masks are created with an appropriate threshold. Conclusion: With this proof-of-concept study, we were able to show the feasibility of working in the k-space frequency domain, preserving phase information, with consistent results. Future research should be dedicated to discovering additional ways the k-space can be used for innovative image analysis and further workflows.Comment: 11 pages, 6 figures, 2 table

Pathologically-Validated Tumor Prediction Maps in MRI

Glioblastoma (GBM) is an aggressive cancer with an average 5-year survival rate of about 5%. Following treatment with surgery, radiation, and chemotherapy, diagnosing tumor recurrence requires serial magnetic resonance imaging (MRI) scans. Infiltrative tumor cells beyond gadolinium enhancement on T1-weighted MRI are difficult to detect. This study therefore aims to improve tumor detection beyond traditional tumor margins. To accomplish this, a neural network model was trained to classify tissue samples as ‘tumor’ or ‘not tumor’. This model was then used to classify thousands of tiles from histology samples acquired at autopsy with known MRI locations on the patient’s final clinical MRI scan. This combined radiological-pathological (rad-path) dataset was then treated as a ground truth to train a second model for predicting tumor presence from MRI alone. Predictive maps were created for seven patients left out of the training steps, and tissue samples were tested to determine the model’s accuracy. The final model produced a receiver operator characteristic (ROC) area under the curve (AUC) of 0.70. This study demonstrates a new method for detecting infiltrative tumor beyond conventional radiologist defined margins based on neural networks applied to rad-path datasets in glioblastoma

Unsupervised learning for vascular heterogeneity assessment of glioblastoma based on magnetic resonance imaging: The Hemodynamic Tissue Signature

[ES] El futuro de la imagen médica está ligado a la inteligencia artificial. El análisis manual de imágenes médicas es hoy en día una tarea ardua, propensa a errores y a menudo inasequible para los humanos, que ha llamado la atención de la comunidad de Aprendizaje Automático (AA). La Imagen por Resonancia Magnética (IRM) nos proporciona una rica variedad de representaciones de la morfología y el comportamiento de lesiones inaccesibles sin una intervención invasiva arriesgada. Sin embargo, explotar la potente pero a menudo latente información contenida en la IRM es una tarea muy complicada, que requiere técnicas de análisis computacional inteligente. Los tumores del sistema nervioso central son una de las enfermedades más críticas estudiadas a través de IRM. Específicamente, el glioblastoma representa un gran desafío, ya que, hasta la fecha, continua siendo un cáncer letal que carece de una terapia satisfactoria. Del conjunto de características que hacen del glioblastoma un tumor tan agresivo, un aspecto particular que ha sido ampliamente estudiado es su heterogeneidad vascular. La fuerte proliferación vascular del glioblastoma, así como su robusta angiogénesis han sido consideradas responsables de la alta letalidad de esta neoplasia. Esta tesis se centra en la investigación y desarrollo del método Hemodynamic Tissue Signature (HTS): un método de AA no supervisado para describir la heterogeneidad vascular de los glioblastomas mediante el análisis de perfusión por IRM. El método HTS se basa en el concepto de hábitat, que se define como una subregión de la lesión con un perfil de IRM que describe un comportamiento fisiológico concreto. El método HTS delinea cuatro hábitats en el glioblastoma: el hábitat HAT, como la región más perfundida del tumor con captación de contraste; el hábitat LAT, como la región del tumor con un perfil angiogénico más bajo; el hábitat IPE, como la región adyacente al tumor con índices de perfusión elevados; y el hábitat VPE, como el edema restante de la lesión con el perfil de perfusión más bajo. La investigación y desarrollo de este método ha originado una serie de contribuciones enmarcadas en esta tesis. Primero, para verificar la fiabilidad de los métodos de AA no supervisados en la extracción de patrones de IRM, se realizó una comparativa para la tarea de segmentación de gliomas de grado alto. Segundo, se propuso un algoritmo de AA no supervisado dentro de la familia de los Spatially Varying Finite Mixture Models. El algoritmo propone una densidad a priori basada en un Markov Random Field combinado con la función probabilística Non-Local Means, para codificar la idea de que píxeles vecinos tienden a pertenecer al mismo objeto. Tercero, se presenta el método HTS para describir la heterogeneidad vascular del glioblastoma. El método se ha aplicado a casos reales en una cohorte local de un solo centro y en una cohorte internacional de más de 180 pacientes de 7 centros europeos. Se llevó a cabo una evaluación exhaustiva del método para medir el potencial pronóstico de los hábitats HTS. Finalmente, la tecnología desarrollada en la tesis se ha integrado en la plataforma online ONCOhabitats (https://www.oncohabitats.upv.es). La plataforma ofrece dos servicios: 1) segmentación de tejidos de glioblastoma, y 2) evaluación de la heterogeneidad vascular del tumor mediante el método HTS. Los resultados de esta tesis han sido publicados en diez contribuciones científicas, incluyendo revistas y conferencias de alto impacto en las áreas de Informática Médica, Estadística y Probabilidad, Radiología y Medicina Nuclear y Aprendizaje Automático. También se emitió una patente industrial registrada en España, Europa y EEUU. Finalmente, las ideas originales concebidas en esta tesis dieron lugar a la creación de ONCOANALYTICS CDX, una empresa enmarcada en el modelo de negocio de los companion diagnostics de compuestos farmacéuticos.[EN] The future of medical imaging is linked to Artificial Intelligence (AI). The manual analysis of medical images is nowadays an arduous, error-prone and often unaffordable task for humans, which has caught the attention of the Machine Learning (ML) community. Magnetic Resonance Imaging (MRI) provides us with a wide variety of rich representations of the morphology and behavior of lesions completely inaccessible without a risky invasive intervention. Nevertheless, harnessing the powerful but often latent information contained in MRI acquisitions is a very complicated task, which requires computational intelligent analysis techniques. Central nervous system tumors are one of the most critical diseases studied through MRI. Specifically, glioblastoma represents a major challenge, as it remains a lethal cancer that, to date, lacks a satisfactory therapy. Of the entire set of characteristics that make glioblastoma so aggressive, a particular aspect that has been widely studied is its vascular heterogeneity. The strong vascular proliferation of glioblastomas, as well as their robust angiogenesis and extensive microvasculature heterogeneity have been claimed responsible for the high lethality of the neoplasm. This thesis focuses on the research and development of the Hemodynamic Tissue Signature (HTS) method: an unsupervised ML approach to describe the vascular heterogeneity of glioblastomas by means of perfusion MRI analysis. The HTS builds on the concept of habitats. A habitat is defined as a sub-region of the lesion with a particular MRI profile describing a specific physiological behavior. The HTS method delineates four habitats within the glioblastoma: the HAT habitat, as the most perfused region of the enhancing tumor; the LAT habitat, as the region of the enhancing tumor with a lower angiogenic profile; the potentially IPE habitat, as the non-enhancing region adjacent to the tumor with elevated perfusion indexes; and the VPE habitat, as the remaining edema of the lesion with the lowest perfusion profile. The research and development of the HTS method has generated a number of contributions to this thesis. First, in order to verify that unsupervised learning methods are reliable to extract MRI patterns to describe the heterogeneity of a lesion, a comparison among several unsupervised learning methods was conducted for the task of high grade glioma segmentation. Second, a Bayesian unsupervised learning algorithm from the family of Spatially Varying Finite Mixture Models is proposed. The algorithm integrates a Markov Random Field prior density weighted by the probabilistic Non-Local Means function, to codify the idea that neighboring pixels tend to belong to the same semantic object. Third, the HTS method to describe the vascular heterogeneity of glioblastomas is presented. The HTS method has been applied to real cases, both in a local single-center cohort of patients, and in an international retrospective cohort of more than 180 patients from 7 European centers. A comprehensive evaluation of the method was conducted to measure the prognostic potential of the HTS habitats. Finally, the technology developed in this thesis has been integrated into an online open-access platform for its academic use. The ONCOhabitats platform is hosted at https://www.oncohabitats.upv.es, and provides two main services: 1) glioblastoma tissue segmentation, and 2) vascular heterogeneity assessment of glioblastomas by means of the HTS method. The results of this thesis have been published in ten scientific contributions, including top-ranked journals and conferences in the areas of Medical Informatics, Statistics and Probability, Radiology & Nuclear Medicine and Machine Learning. An industrial patent registered in Spain, Europe and EEUU was also issued. Finally, the original ideas conceived in this thesis led to the foundation of ONCOANALYTICS CDX, a company framed into the business model of companion diagnostics for pharmaceutical compounds.[CA] El futur de la imatge mèdica està lligat a la intel·ligència artificial. L'anàlisi manual d'imatges mèdiques és hui dia una tasca àrdua, propensa a errors i sovint inassequible per als humans, que ha cridat l'atenció de la comunitat d'Aprenentatge Automàtic (AA). La Imatge per Ressonància Magnètica (IRM) ens proporciona una àmplia varietat de representacions de la morfologia i el comportament de lesions inaccessibles sense una intervenció invasiva arriscada. Tanmateix, explotar la potent però sovint latent informació continguda a les adquisicions de IRM esdevé una tasca molt complicada, que requereix tècniques d'anàlisi computacional intel·ligent. Els tumors del sistema nerviós central són una de les malalties més crítiques estudiades a través de IRM. Específicament, el glioblastoma representa un gran repte, ja que, fins hui, continua siguent un càncer letal que manca d'una teràpia satisfactòria. Del conjunt de característiques que fan del glioblastoma un tumor tan agressiu, un aspecte particular que ha sigut àmpliament estudiat és la seua heterogeneïtat vascular. La forta proliferació vascular dels glioblastomes, així com la seua robusta angiogènesi han sigut considerades responsables de l'alta letalitat d'aquesta neoplàsia. Aquesta tesi es centra en la recerca i desenvolupament del mètode Hemodynamic Tissue Signature (HTS): un mètode d'AA no supervisat per descriure l'heterogeneïtat vascular dels glioblastomas mitjançant l'anàlisi de perfusió per IRM. El mètode HTS es basa en el concepte d'hàbitat, que es defineix com una subregió de la lesió amb un perfil particular d'IRM, que descriu un comportament fisiològic concret. El mètode HTS delinea quatre hàbitats dins del glioblastoma: l'hàbitat HAT, com la regió més perfosa del tumor amb captació de contrast; l'hàbitat LAT, com la regió del tumor amb un perfil angiogènic més baix; l'hàbitat IPE, com la regió adjacent al tumor amb índexs de perfusió elevats, i l'hàbitat VPE, com l'edema restant de la lesió amb el perfil de perfusió més baix. La recerca i desenvolupament del mètode HTS ha originat una sèrie de contribucions emmarcades a aquesta tesi. Primer, per verificar la fiabilitat dels mètodes d'AA no supervisats en l'extracció de patrons d'IRM, es va realitzar una comparativa en la tasca de segmentació de gliomes de grau alt. Segon, s'ha proposat un algorisme d'AA no supervisat dintre de la família dels Spatially Varying Finite Mixture Models. L'algorisme proposa un densitat a priori basada en un Markov Random Field combinat amb la funció probabilística Non-Local Means, per a codificar la idea que els píxels veïns tendeixen a pertànyer al mateix objecte semàntic. Tercer, es presenta el mètode HTS per descriure l'heterogeneïtat vascular dels glioblastomas. El mètode HTS s'ha aplicat a casos reals en una cohort local d'un sol centre i en una cohort internacional de més de 180 pacients de 7 centres europeus. Es va dur a terme una avaluació exhaustiva del mètode per mesurar el potencial pronòstic dels hàbitats HTS. Finalment, la tecnologia desenvolupada en aquesta tesi s'ha integrat en una plataforma online ONCOhabitats (https://www.oncohabitats.upv.es). La plataforma ofereix dos serveis: 1) segmentació dels teixits del glioblastoma, i 2) avaluació de l'heterogeneïtat vascular dels glioblastomes mitjançant el mètode HTS. Els resultats d'aquesta tesi han sigut publicats en deu contribucions científiques, incloent revistes i conferències de primer nivell a les àrees d'Informàtica Mèdica, Estadística i Probabilitat, Radiologia i Medicina Nuclear i Aprenentatge Automàtic. També es va emetre una patent industrial registrada a Espanya, Europa i els EEUU. Finalment, les idees originals concebudes en aquesta tesi van donar lloc a la creació d'ONCOANALYTICS CDX, una empresa emmarcada en el model de negoci dels companion diagnostics de compostos farmacèutics.En este sentido quiero agradecer a las diferentes instituciones y estructuras de financiación de investigación que han contribuido al desarrollo de esta tesis. En especial quiero agradecer a la Universitat Politècnica de València, donde he desarrollado toda mi carrera acadèmica y científica, así como al Ministerio de Ciencia e Innovación, al Ministerio de Economía y Competitividad, a la Comisión Europea, al EIT Health Programme y a la fundación Caixa ImpulseJuan Albarracín, J. (2020). Unsupervised learning for vascular heterogeneity assessment of glioblastoma based on magnetic resonance imaging: The Hemodynamic Tissue Signature [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/149560TESI

Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification

Automatic brain tumour segmentation has become a key component for the future of brain tumour treatment. Currently, most of brain tumour segmentation approaches arise from the supervised learning standpoint, which requires a labelled training dataset from which to infer the models of the classes. The performance of these models is directly determined by the size and quality of the training corpus, whose retrieval becomes a tedious and time-consuming task. On the other hand, unsupervised approaches avoid these limitations but often do not reach comparable results than the supervised methods. In this sense, we propose an automated unsupervised method for brain tumour segmentation based on anatomical Magnetic Resonance (MR) images. Four unsupervised classification algorithms, grouped by their structured or non-structured condition, were evaluated within our pipeline. Considering the non-structured algorithms, we evaluated K-means, Fuzzy K-means and Gaussian Mixture Model (GMM), whereas as structured classification algorithms we evaluated Gaussian Hidden Markov Random Field (GHMRF). An automated postprocess based on a statistical approach supported by tissue probability maps is proposed to automatically identify the tumour classes after the segmentations. We evaluated our brain tumour segmentation method with the public BRAin Tumor Segmentation (BRATS) 2013 Test and Leaderboard datasets. Our approach based on the GMM model improves the results obtained by most of the supervised methods evaluated with the Leaderboard set and reaches the second position in the ranking. Our variant based on the GHMRF achieves the first position in the Test ranking of the unsupervised approaches and the seventh position in the general Test ranking, which confirms the method as a viable alternative for brain tumour segmentation.EFG was supported by Programa Torres Quevedo, Ministerio de Educacion y Ciencia, co-funded by the European Social Fund (PTQ-1205693). EFG, JMGG, and JVM were supported by Red Tematica de Investigacion Cooperativa en Cancer, (RTICC) 2013-2016 (RD12/0036/0020). JMGG was supported by Project TIN2013-43457-R: Caracterizacion de firmas biologicas de glioblastomas mediante modelos no-supervisados de prediccion estructurada basados en biomarcadores de imagen, co-funded by the Ministerio de Economia y Competitividad of Spain; CON2014001 UPV-IISLaFe: Unsupervised glioblastoma tumor components segmentation based on perfusion multiparametric MRI and spatio/temporal constraints; and CON2014002 UPV-IISLaFe: Empleo de segmentacion no supervisada multiparametrica basada en perfusion RM para la caracterizacion del edema peritumoral de gliomas y metastasis cerebrales unicas, funded by Instituto de Investigacion Sanitaria H. Universitario y Politecnico La Fe. This work was partially supported by the Instituto de Aplicaciones de las Tecnologias de la Informacion y las Comunicaciones Avanzadas (ITACA). Veratech for Health S.L. provided support in the form of salaries for author EF-G, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author is articulated in the "author contributions" section. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.Juan Albarracín, J.; Fuster García, E.; Manjón Herrera, JV.; Robles Viejo, M.; Aparici, F.; Marti-Bonmati, L.; García Gómez, JM. (2015). Automated Glioblastoma Segmentation Based on a Multiparametric Structured Unsupervised Classification. PLoS ONE. 10(5):1-20. https://doi.org/10.1371/journal.pone.0125143S120105Wen, P. Y., Macdonald, D. R., Reardon, D. A., Cloughesy, T. F., Sorensen, A. G., Galanis, E., … Chang, S. M. (2010). Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. Journal of Clinical Oncology, 28(11), 1963-1972. doi:10.1200/jco.2009.26.3541Bauer, S., Wiest, R., Nolte, L.-P., & Reyes, M. (2013). A survey of MRI-based medical image analysis for brain tumor studies. Physics in Medicine and Biology, 58(13), R97-R129. doi:10.1088/0031-9155/58/13/r97Dolecek, T. A., Propp, J. M., Stroup, N. E., & Kruchko, C. (2012). CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2005-2009. Neuro-Oncology, 14(suppl 5), v1-v49. doi:10.1093/neuonc/nos218Gordillo, N., Montseny, E., & Sobrevilla, P. (2013). State of the art survey on MRI brain tumor segmentation. Magnetic Resonance Imaging, 31(8), 1426-1438. doi:10.1016/j.mri.2013.05.002Verma, R., Zacharaki, E. I., Ou, Y., Cai, H., Chawla, S., Lee, S.-K., … Davatzikos, C. (2008). Multiparametric Tissue Characterization of Brain Neoplasms and Their Recurrence Using Pattern Classification of MR Images. Academic Radiology, 15(8), 966-977. doi:10.1016/j.acra.2008.01.029Jensen, T. R., & Schmainda, K. M. (2009). Computer-aided detection of brain tumor invasion using multiparametric MRI. Journal of Magnetic Resonance Imaging, 30(3), 481-489. doi:10.1002/jmri.21878Breiman, L. (2001). Machine Learning, 45(1), 5-32. doi:10.1023/a:1010933404324Wagstaff KL. Intelligent Clustering with instance-level constraints. PhD Thesis, Cornell University. 2002.Fletcher-Heath, L. M., Hall, L. O., Goldgof, D. B., & Murtagh, F. R. (2001). Automatic segmentation of non-enhancing brain tumors in magnetic resonance images. Artificial Intelligence in Medicine, 21(1-3), 43-63. doi:10.1016/s0933-3657(00)00073-7Nie, J., Xue, Z., Liu, T., Young, G. S., Setayesh, K., Guo, L., & Wong, S. T. C. (2009). Automated brain tumor segmentation using spatial accuracy-weighted hidden Markov Random Field. Computerized Medical Imaging and Graphics, 33(6), 431-441. doi:10.1016/j.compmedimag.2009.04.006Zhu, Y., Young, G. S., Xue, Z., Huang, R. Y., You, H., Setayesh, K., … Wong, S. T. (2012). Semi-Automatic Segmentation Software for Quantitative Clinical Brain Glioblastoma Evaluation. Academic Radiology, 19(8), 977-985. doi:10.1016/j.acra.2012.03.026Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a hidden Markov random field model and the expectation-maximization algorithm. IEEE Transactions on Medical Imaging, 20(1), 45-57. doi:10.1109/42.906424Vijayakumar, C., Damayanti, G., Pant, R., & Sreedhar, C. M. (2007). Segmentation and grading of brain tumors on apparent diffusion coefficient images using self-organizing maps. Computerized Medical Imaging and Graphics, 31(7), 473-484. doi:10.1016/j.compmedimag.2007.04.004Prastawa, M., Bullitt, E., Moon, N., Van Leemput, K., & Gerig, G. (2003). Automatic brain tumor segmentation by subject specific modification of atlas priors1. Academic Radiology, 10(12), 1341-1348. doi:10.1016/s1076-6332(03)00506-3Gudbjartsson, H., & Patz, S. (1995). The rician distribution of noisy mri data. Magnetic Resonance in Medicine, 34(6), 910-914. doi:10.1002/mrm.1910340618Buades, A., Coll, B., & Morel, J. M. (2005). A Review of Image Denoising Algorithms, with a New One. Multiscale Modeling & Simulation, 4(2), 490-530. doi:10.1137/040616024Manjón, J. V., Coupé, P., Martí-Bonmatí, L., Collins, D. L., & Robles, M. (2009). Adaptive non-local means denoising of MR images with spatially varying noise levels. Journal of Magnetic Resonance Imaging, 31(1), 192-203. doi:10.1002/jmri.22003Sled, J. G., Zijdenbos, A. P., & Evans, A. C. (1998). A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Transactions on Medical Imaging, 17(1), 87-97. doi:10.1109/42.668698Tustison, N. J., Avants, B. B., Cook, P. A., Yuanjie Zheng, Egan, A., Yushkevich, P. A., & Gee, J. C. (2010). N4ITK: Improved N3 Bias Correction. IEEE Transactions on Medical Imaging, 29(6), 1310-1320. doi:10.1109/tmi.2010.2046908Manjón, J. V., Coupé, P., Buades, A., Collins, D. L., & Robles, M. (2010). MRI Superresolution Using Self-Similarity and Image Priors. International Journal of Biomedical Imaging, 2010, 1-11. doi:10.1155/2010/425891Rousseau, F. (2010). A non-local approach for image super-resolution using intermodality priors☆. Medical Image Analysis, 14(4), 594-605. doi:10.1016/j.media.2010.04.005Protter, M., Elad, M., Takeda, H., & Milanfar, P. (2009). Generalizing the Nonlocal-Means to Super-Resolution Reconstruction. IEEE Transactions on Image Processing, 18(1), 36-51. doi:10.1109/tip.2008.2008067Manjón, J. V., Coupé, P., Buades, A., Fonov, V., Louis Collins, D., & Robles, M. (2010). Non-local MRI upsampling. Medical Image Analysis, 14(6), 784-792. doi:10.1016/j.media.2010.05.010Kassner, A., & Thornhill, R. E. (2010). Texture Analysis: A Review of Neurologic MR Imaging Applications. American Journal of Neuroradiology, 31(5), 809-816. doi:10.3174/ajnr.a2061Ahmed, S., Iftekharuddin, K. M., & Vossough, A. (2011). Efficacy of Texture, Shape, and Intensity Feature Fusion for Posterior-Fossa Tumor Segmentation in MRI. IEEE Transactions on Information Technology in Biomedicine, 15(2), 206-213. doi:10.1109/titb.2011.2104376Lloyd, S. (1982). Least squares quantization in PCM. IEEE Transactions on Information Theory, 28(2), 129-137. doi:10.1109/tit.1982.1056489Dunn, J. C. (1973). A Fuzzy Relative of the ISODATA Process and Its Use in Detecting Compact Well-Separated Clusters. Journal of Cybernetics, 3(3), 32-57. doi:10.1080/01969727308546046Bezdek, J. C. (1981). Pattern Recognition with Fuzzy Objective Function Algorithms. doi:10.1007/978-1-4757-0450-1Hammersley, JM, Clifford, P. Markov fields on finite graphs and lattices. 1971.Komodakis, N., & Tziritas, G. (2007). Approximate Labeling via Graph Cuts Based on Linear Programming. IEEE Transactions on Pattern Analysis and Machine Intelligence, 29(8), 1436-1453. doi:10.1109/tpami.2007.1061Komodakis, N., Tziritas, G., & Paragios, N. (2008). Performance vs computational efficiency for optimizing single and dynamic MRFs: Setting the state of the art with primal-dual strategies. Computer Vision and Image Understanding, 112(1), 14-29. doi:10.1016/j.cviu.2008.06.007Fonov, V., Evans, A. C., Botteron, K., Almli, C. R., McKinstry, R. C., & Collins, D. L. (2011). Unbiased average age-appropriate atlases for pediatric studies. NeuroImage, 54(1), 313-327. doi:10.1016/j.neuroimage.2010.07.033Fonov, V., Evans, A., McKinstry, R., Almli, C., & Collins, D. (2009). Unbiased nonlinear average age-appropriate brain templates from birth to adulthood. NeuroImage, 47, S102. doi:10.1016/s1053-8119(09)70884-5Klein, A., Andersson, J., Ardekani, B. A., Ashburner, J., Avants, B., Chiang, M.-C., … Parsey, R. V. (2009). Evaluation of 14 nonlinear deformation algorithms applied to human brain MRI registration. NeuroImage, 46(3), 786-802. doi:10.1016/j.neuroimage.2008.12.037AVANTS, B., EPSTEIN, C., GROSSMAN, M., & GEE, J. (2008). Symmetric diffeomorphic image registration with cross-correlation: Evaluating automated labeling of elderly and neurodegenerative brain. Medical Image Analysis, 12(1), 26-41. doi:10.1016/j.media.2007.06.004Saez C, Robles M, Garcia-Gomez JM. Stability metrics for multi-source biomedical data based on simplicial projections from probability distribution distances. Statistical Methods in Medical Research 2014; In press