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  1. Book ; Online: CIMIL-CRC

    Hezi, Hadar / Gelber, Matan / Balabanov, Alexander / Maruvka, Yosef E. / Freiman, Moti

    a clinically-informed multiple instance learning framework for patient-level colorectal cancer molecular subtypes classification from H\&E stained images

    2024  

    Abstract: Treatment approaches for colorectal cancer (CRC) are highly dependent on the molecular subtype, as immunotherapy has shown efficacy in cases with microsatellite instability (MSI) but is ineffective for the microsatellite stable (MSS) subtype. There is ... ...

    Abstract Treatment approaches for colorectal cancer (CRC) are highly dependent on the molecular subtype, as immunotherapy has shown efficacy in cases with microsatellite instability (MSI) but is ineffective for the microsatellite stable (MSS) subtype. There is promising potential in utilizing deep neural networks (DNNs) to automate the differentiation of CRC subtypes by analyzing Hematoxylin and Eosin (H\&E) stained whole-slide images (WSIs). Due to the extensive size of WSIs, Multiple Instance Learning (MIL) techniques are typically explored. However, existing MIL methods focus on identifying the most representative image patches for classification, which may result in the loss of critical information. Additionally, these methods often overlook clinically relevant information, like the tendency for MSI class tumors to predominantly occur on the proximal (right side) colon. We introduce `CIMIL-CRC', a DNN framework that: 1) solves the MSI/MSS MIL problem by efficiently combining a pre-trained feature extraction model with principal component analysis (PCA) to aggregate information from all patches, and 2) integrates clinical priors, particularly the tumor location within the colon, into the model to enhance patient-level classification accuracy. We assessed our CIMIL-CRC method using the average area under the curve (AUC) from a 5-fold cross-validation experimental setup for model development on the TCGA-CRC-DX cohort, contrasting it with a baseline patch-level classification, MIL-only approach, and Clinically-informed patch-level classification approach. Our CIMIL-CRC outperformed all methods (AUROC: $0.92\pm0.002$ (95\% CI 0.91-0.92), vs. $0.79\pm0.02$ (95\% CI 0.76-0.82), $0.86\pm0.01$ (95\% CI 0.85-0.88), and $0.87\pm0.01$ (95\% CI 0.86-0.88), respectively). The improvement was statistically significant.
    Keywords Computer Science - Computer Vision and Pattern Recognition
    Subject code 004 ; 006
    Publishing date 2024-01-29
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Analyzing Frequently Mutated Genes and the Association With Tumor Mutation Load.

    Maruvka, Yosef E / Haradhvala, Nicholas J / Getz, Gad

    JAMA oncology

    2019  Volume 5, Issue 4, Page(s) 577

    MeSH term(s) CA-125 Antigen ; Humans ; Membrane Proteins ; Mutation ; Stomach Neoplasms ; Tumor Burden
    Chemical Substances CA-125 Antigen ; MUC16 protein, human ; Membrane Proteins
    Language English
    Publishing date 2019-03-07
    Publishing country United States
    Document type Journal Article ; Comment
    ISSN 2374-2445
    ISSN (online) 2374-2445
    DOI 10.1001/jamaoncol.2019.0127
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Book ; Online: Exploring the Interplay Between Colorectal Cancer Subtypes Genomic Variants and Cellular Morphology

    Hezi, Hadar / Shats, Daniel / Gurevich, Daniel / Maruvka, Yosef E. / Freiman, Moti

    A Deep-Learning Approach

    2023  

    Abstract: Molecular subtypes of colorectal cancer (CRC) significantly influence treatment decisions. While convolutional neural networks (CNNs) have recently been introduced for automated CRC subtype identification using H&E stained histopathological images, the ... ...

    Abstract Molecular subtypes of colorectal cancer (CRC) significantly influence treatment decisions. While convolutional neural networks (CNNs) have recently been introduced for automated CRC subtype identification using H&E stained histopathological images, the correlation between CRC subtype genomic variants and their corresponding cellular morphology expressed by their imaging phenotypes is yet to be fully explored. The goal of this study was to determine such correlations by incorporating genomic variants in CNN models for CRC subtype classification from H&E images. We utilized the publicly available TCGA-CRC-DX dataset, which comprises whole slide images from 360 CRC-diagnosed patients (260 for training and 100 for testing). This dataset also provides information on CRC subtype classifications and genomic variations. We trained CNN models for CRC subtype classification that account for potential correlation between genomic variations within CRC subtypes and their corresponding cellular morphology patterns. We assessed the interplay between CRC subtypes' genomic variations and cellular morphology patterns by evaluating the CRC subtype classification accuracy of the different models in a stratified 5-fold cross-validation experimental setup using the area under the ROC curve (AUROC) and average precision (AP) as the performance metrics. Combining the CNN models account for variations in CIMP and SNP further improved classification accuracy (AUROC: 0.847$\pm$0.01 vs. 0.787$\pm$0.03, p$=$0.01, AP: 0.68$\pm$0.02 vs. 0.64$\pm$0.05).
    Keywords Computer Science - Computer Vision and Pattern Recognition
    Subject code 006
    Publishing date 2023-03-26
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Book ; Online: Patient-level Microsatellite Stability Assessment from Whole Slide Images By Combining Momentum Contrast Learning and Group Patch Embeddings

    Shats, Daniel / Hezi, Hadar / Shani, Guy / Maruvka, Yosef E. / Freiman, Moti

    2022  

    Abstract: Assessing microsatellite stability status of a patient's colorectal cancer is crucial in personalizing treatment regime. Recently, convolutional-neural-networks (CNN) combined with transfer-learning approaches were proposed to circumvent traditional ... ...

    Abstract Assessing microsatellite stability status of a patient's colorectal cancer is crucial in personalizing treatment regime. Recently, convolutional-neural-networks (CNN) combined with transfer-learning approaches were proposed to circumvent traditional laboratory testing for determining microsatellite status from hematoxylin and eosin stained biopsy whole slide images (WSI). However, the high resolution of WSI practically prevent direct classification of the entire WSI. Current approaches bypass the WSI high resolution by first classifying small patches extracted from the WSI, and then aggregating patch-level classification logits to deduce the patient-level status. Such approaches limit the capacity to capture important information which resides at the high resolution WSI data. We introduce an effective approach to leverage WSI high resolution information by momentum contrastive learning of patch embeddings along with training a patient-level classifier on groups of those embeddings. Our approach achieves up to 7.4\% better accuracy compared to the straightforward patch-level classification and patient level aggregation approach with a higher stability (AUC, $0.91 \pm 0.01$ vs. $0.85 \pm 0.04$, p-value$<0.01$). Our code can be found at https://github.com/TechnionComputationalMRILab/colorectal_cancer_ai.

    Comment: To appear in the proceedings of the ECCV workshop on Medical Computer Vision (ECCV-MCV 2022). Link: https://mcv-workshop.github.io/
    Keywords Computer Science - Computer Vision and Pattern Recognition ; Computer Science - Artificial Intelligence ; Computer Science - Machine Learning ; Quantitative Biology - Quantitative Methods
    Subject code 006
    Publishing date 2022-08-22
    Publishing country us
    Document type Book ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: First principles theories for last name dynamics.

    Maruvka, Yosef E / Shnerb, Nadav M

    Physics of life reviews

    2013  Volume 10, Issue 4, Page(s) 422–3; discussion 426–7

    MeSH term(s) Genetics, Population/methods ; Humans ; Names ; Physics/methods ; Statistics as Topic/methods
    Language English
    Publishing date 2013-12
    Publishing country Netherlands
    Document type Comment ; Journal Article
    ZDB-ID 2148883-6
    ISSN 1873-1457 ; 1571-0645
    ISSN (online) 1873-1457
    ISSN 1571-0645
    DOI 10.1016/j.plrev.2013.07.024
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Di-genic inheritance of germline POLE and PMS2 pathogenic variants causes a unique condition associated with pediatric cancer predisposition.

    Michaeli, Orli / Ladany, Hagay / Erez, Ayelet / Ben Shachar, Shay / Izraeli, Shai / Lidzbarsky, Gabriel / Basel-Salmon, Lina / Biskup, Saskia / Maruvka, Yosef E / Toledano, Helen / Goldberg, Yael

    Clinical genetics

    2022  Volume 101, Issue 4, Page(s) 442–447

    Abstract: Polymerase proofreading-associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult-onset cancer. PPAP and MMR-deficient tumors are both hypermutated, and each has a ... ...

    Abstract Polymerase proofreading-associated polyposis (PPAP) and Lynch syndrome, caused by mutated POLE and mismatch repair (MMR) genes, respectively, are associated with adult-onset cancer. PPAP and MMR-deficient tumors are both hypermutated, and each has a unique mutational signature. We describe a 4.5-year-old boy with multiple café au lait spots who presented with metastatic Sonic Hedgehog-activated medulloblastoma, with partial response to intensive chemotherapy and immunotherapy. The tumor showed microsatellite stability, loss of PMS2 nuclear expression, and an exceptionally high tumor mutational burden of 276 Mut/Mb. Germline molecular analysis revealed an inherited heterozygous pathogenic POLE variant and a de novo heterozygous PMS2 pathogenic variant. The tumor featured the MMR, POLE, and POLE+MMR mutational signatures. This is the first description of a di-genic condition, which we named "POL-LYNCH syndrome," manifested by an aggressive ultra-mutant pediatric medulloblastoma with a unique genomic signature.
    MeSH term(s) Cerebellar Neoplasms/complications ; Cerebellar Neoplasms/genetics ; Child, Preschool ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics ; DNA Mismatch Repair/genetics ; DNA Polymerase II/genetics ; DNA-Binding Proteins/genetics ; Germ-Line Mutation/genetics ; Hedgehog Proteins/genetics ; Humans ; Male ; Medulloblastoma/genetics ; Mismatch Repair Endonuclease PMS2/genetics ; Poly-ADP-Ribose Binding Proteins/genetics
    Chemical Substances DNA-Binding Proteins ; Hedgehog Proteins ; Poly-ADP-Ribose Binding Proteins ; DNA Polymerase II (EC 2.7.7.7) ; POLE protein, human (EC 2.7.7.7) ; PMS2 protein, human (EC 3.6.1.-) ; Mismatch Repair Endonuclease PMS2 (EC 3.6.1.3)
    Language English
    Publishing date 2022-01-07
    Publishing country Denmark
    Document type Case Reports ; Journal Article
    ZDB-ID 221209-2
    ISSN 1399-0004 ; 0009-9163
    ISSN (online) 1399-0004
    ISSN 0009-9163
    DOI 10.1111/cge.14106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: On the validity of using increases in 5-year survival rates to measure success in the fight against cancer.

    Maruvka, Yosef E / Tang, Min / Michor, Franziska

    PloS one

    2014  Volume 9, Issue 7, Page(s) e83100

    Abstract: Background: The 5-year survival rate of cancer patients is the most commonly used statistic to reflect improvements in the war against cancer. This idea, however, was refuted based on an analysis showing that changes in 5-year survival over time bear no ...

    Abstract Background: The 5-year survival rate of cancer patients is the most commonly used statistic to reflect improvements in the war against cancer. This idea, however, was refuted based on an analysis showing that changes in 5-year survival over time bear no relationship with changes in cancer mortality.
    Methods: Here we show that progress in the fight against cancer can be evaluated by analyzing the association between 5-year survival rates and mortality rates normalized by the incidence (mortality over incidence, MOI). Changes in mortality rates are caused by improved clinical management as well as changing incidence rates, and since the latter can mask the effects of the former, it can also mask the correlation between survival and mortality rates. However, MOI is a more robust quantity and reflects improvements in cancer outcomes by overcoming the masking effect of changing incidence rates. Using population-based statistics for the US and the European Nordic countries, we determined the association of changes in 5-year survival rates and MOI.
    Results: We observed a strong correlation between changes in 5-year survival rates of cancer patients and changes in the MOI for all the countries tested. This finding demonstrates that there is no reason to assume that the improvements in 5-year survival rates are artificial. We obtained consistent results when examining the subset of cancer types whose incidence did not increase, suggesting that over-diagnosis does not obscure the results.
    Conclusions: We have demonstrated, via the negative correlation between changes in 5-year survival rates and changes in MOI, that increases in 5-year survival rates reflect real improvements over time made in the clinical management of cancer. Furthermore, we found that increases in 5-year survival rates are not predominantly artificial byproducts of lead-time bias, as implied in the literature. The survival measure alone can therefore be used for a rough approximation of the amount of progress in the clinical management of cancer, but should ideally be used with other measures.
    MeSH term(s) Disease-Free Survival ; Humans ; Incidence ; Mass Screening ; Neoplasms/epidemiology ; Neoplasms/mortality ; Outcome Assessment, Health Care/methods ; Registries ; Survival Analysis ; Survival Rate
    Language English
    Publishing date 2014-07-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0083100
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Polymorphism data can reveal the origin of species abundance statistics.

    Maruvka, Yosef E / Shnerb, Nadav M

    PLoS computational biology

    2009  Volume 5, Issue 4, Page(s) e1000359

    Abstract: What is the underlying mechanism behind the fat-tailed statistics observed for species abundance distributions? The two main hypotheses in the field are the adaptive (niche) theories, where species abundance reflects its fitness, and the neutral theory ... ...

    Abstract What is the underlying mechanism behind the fat-tailed statistics observed for species abundance distributions? The two main hypotheses in the field are the adaptive (niche) theories, where species abundance reflects its fitness, and the neutral theory that assumes demographic stochasticity as the main factor determining community structure. Both explanations suggest quite similar species-abundance distributions, but very different histories: niche scenarios assume that a species population in the past was similar to the observed one, while neutral scenarios are characterized by strongly fluctuating populations. Since the genetic variations within a population depend on its abundance in the past, we present here a way to discriminate between the theories using the genetic diversity of noncoding DNA. A statistical test, based on the Fu-Li method, has been developed and enables such a differentiation. We have analyzed the results gathered from individual-based simulation of both types of histories and obtained clear distinction between the Fu-Li statistics of the neutral scenario and that of the niche scenario. Our results suggest that data for 10-50 species, with approximately 30 sequenced individuals for each species, may allow one to distinguish between these two theories.
    MeSH term(s) Animals ; Biological Evolution ; Evolution, Molecular ; Genetic Variation/genetics ; Genetics, Population ; Humans ; Models, Statistical ; Origin of Life ; Polymorphism, Single Nucleotide/genetics
    Language English
    Publishing date 2009-04-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2193340-6
    ISSN 1553-7358 ; 1553-734X
    ISSN (online) 1553-7358
    ISSN 1553-734X
    DOI 10.1371/journal.pcbi.1000359
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Neutral dynamics and cluster statistics in a tropical forest.

    Seri, Efrat / Maruvka, Yosef E / Shnerb, Nadav M

    The American naturalist

    2012  Volume 180, Issue 6, Page(s) E161–73

    Abstract: The neutral theory of biodiversity attributes community structure to the effects of chance alone, assuming that all species and individuals are demographically equivalent. Here we present a spatially explicit version of the neutral theory and test it ... ...

    Abstract The neutral theory of biodiversity attributes community structure to the effects of chance alone, assuming that all species and individuals are demographically equivalent. Here we present a spatially explicit version of the neutral theory and test it against the Barro Colorado Island (BCI) data. Monitoring the dynamics of clusters, we show that the effect of local heterogeneities (e.g., microtopography) is weak, making a spatially homogenous model plausible. We then compare the cluster statistics of the three most frequent species with the patterns obtained from neutral dynamics, examining two families of recruitment kernels: one that interpolates between a limited distance and panmictic dispersal (local-global) and one that assumes a scale-free Cauchy kernel. The results rule out the local-global dispersal model and show that the spatial patterns fit very nicely those obtained from the fat-tailed kernel. Our work emphasizes the importance of spatiotemporal cluster dynamics as an instrument for detecting the factors that govern community assembly.
    MeSH term(s) Annonaceae/physiology ; Biodiversity ; Cluster Analysis ; Ecosystem ; Models, Biological ; Panama ; Plant Dispersal ; Population Dynamics ; Rubiaceae/physiology ; Trees/physiology ; Tropical Climate ; Violaceae/physiology
    Language English
    Publishing date 2012-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 207092-3
    ISSN 1537-5323 ; 0003-0147
    ISSN (online) 1537-5323
    ISSN 0003-0147
    DOI 10.1086/668125
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Nonlocal competition and front propagation in branching-coalescence systems.

    Maruvka, Yosef E / Shnerb, Nadav M

    Physical review. E, Statistical, nonlinear, and soft matter physics

    2007  Volume 75, Issue 4 Pt 1, Page(s) 42901

    Abstract: The spatial invasion of a stable into an unstable phase is studied for the branching-coalescence process with nonlocal competition. Numerical experiments show that the threshold at the front leading edge, introduced by the discreteness of the reactants, ... ...

    Abstract The spatial invasion of a stable into an unstable phase is studied for the branching-coalescence process with nonlocal competition. Numerical experiments show that the threshold at the front leading edge, introduced by the discreteness of the reactants, allows for the nonlocal competition to affect the front velocity. However, the front still moves ballistically after a short transient period for any finite range competition length.
    Language English
    Publishing date 2007-04
    Publishing country United States
    Document type Journal Article
    ISSN 1539-3755
    ISSN 1539-3755
    DOI 10.1103/PhysRevE.75.042901
    Database MEDical Literature Analysis and Retrieval System OnLINE

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