Joseph Paul Cohen

T. Hoang

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors,… (see more) together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

2022-03-24

Frontiers in Immunology (published)

Monoallelic Heb/Tcf12 Deletion Reduces the Requirement for NOTCH1 Hyperactivation in T-Cell Acute Lymphoblastic Leukemia

Diogo F. T. Veiga

Mathieu Tremblay

Bastien Gerby

Sabine Herblot

André Haman

Patrick Gendron

Sébastien Lemieux

Juan Carlos Zúñiga-Pflücker

Josée Hébert

Trang Hoang

Early T-cell development is precisely controlled by E proteins, that indistinguishably include HEB/TCF12 and E2A/TCF3 transcription factors,… (see more) together with NOTCH1 and pre-T cell receptor (TCR) signalling. Importantly, perturbations of early T-cell regulatory networks are implicated in leukemogenesis. NOTCH1 gain of function mutations invariably lead to T-cell acute lymphoblastic leukemia (T-ALL), whereas inhibition of E proteins accelerates leukemogenesis. Thus, NOTCH1, pre-TCR, E2A and HEB functions are intertwined, but how these pathways contribute individually or synergistically to leukemogenesis remain to be documented. To directly address these questions, we leveraged Cd3e-deficient mice in which pre-TCR signaling and progression through β-selection is abrogated to dissect and decouple the roles of pre-TCR, NOTCH1, E2A and HEB in SCL/TAL1-induced T-ALL, via the use of Notch1 gain of function transgenic (Notch1ICtg) and Tcf12+/- or Tcf3+/- heterozygote mice. As a result, we now provide evidence that both HEB and E2A restrain cell proliferation at the β-selection checkpoint while the clonal expansion of SCL-LMO1-induced pre-leukemic stem cells in T-ALL is uniquely dependent on Tcf12 gene dosage. At the molecular level, HEB protein levels are decreased via proteasomal degradation at the leukemic stage, pointing to a reversible loss of function mechanism. Moreover, in SCL-LMO1-induced T-ALL, loss of one Tcf12 allele is sufficient to bypass pre-TCR signaling which is required for Notch1 gain of function mutations and for progression to T-ALL. In contrast, Tcf12 monoallelic deletion does not accelerate Notch1IC-induced T-ALL, indicating that Tcf12 and Notch1 operate in the same pathway. Finally, we identify a tumor suppressor gene set downstream of HEB, exhibiting significantly lower expression levels in pediatric T-ALL compared to B-ALL and brain cancer samples, the three most frequent pediatric cancers. In summary, our results indicate a tumor suppressor function of HEB/TCF12 in T-ALL to mitigate cell proliferation controlled by NOTCH1 in pre-leukemic stem cells and prevent NOTCH1-driven progression to T-ALL.

2022-03-24

Frontiers in Immunology (published)

Multi-Domain Balanced Sampling Improves Out-of-Distribution Generalization of Chest X-ray Pathology Prediction Models

Enoch Amoatey Tetteh

Joseph D Viviano

David Scott Krueger

Learning models that generalize under different distribution shifts in medical imaging has been a long-standing research challenge. There ha… (see more)ve been several proposals for efficient and robust visual representation learning among vision research practitioners, especially in the sensitive and critical biomedical domain. In this paper, we propose an idea for out-of-distribution generalization of chest X-ray pathologies that uses a simple balanced batch sampling technique. We observed that balanced sampling between the multiple training datasets improves the performance over baseline models trained without balancing.

2021-12-27

ArXiv (preprint)

arxiv.org

Problèmes associés au déploiement des modèles fondés sur l’apprentissage machine en santé

Tianshi Cao

Joseph D Viviano

Chin-wei Huang

Michael Fralick

Marzyeh Ghassemi

Muhammad Mamdani

Russell Greiner

2021-11-07

Canadian Medical Association Journal (published)

Problems in the deployment of machine-learned models in health care

Tianshi Cao

Joseph D Viviano

Chinwei Huang

Michael Fralick

Marzyeh Ghassemi

M. Mamdani

R. Greiner

2021-08-30

Canadian Medical Association Journal (published)

Exploring the Wasserstein metric for survival analysis

Tristan Sylvain

Margaux Luck

Andrea Lodi

Survival analysis is a type of semi-supervised task where the target output (the survival time) is often right-censored. Utilizing this info… (see more)rmation is a challenge because it is not obvious how to correctly incorporate these censored examples into a model. We study how three categories of loss functions can take advantage of this information: partial likelihood methods, rank methods, and our own classiﬁcation method based on a Wasserstein metric (WM) and the non-parametric Kaplan Meier (KM) estimate of the probability density to impute the labels of censored examples. The proposed method predicts the probability distribution of an event, letting us compute survival curves and expected times of survival that are easier to interpret than the rank. We also demonstrate that this approach directly optimizes the expected C-index which is the most common evaluation metric for survival models.

Exploring the Wasserstein metric for time-to-event analysis.

Tristan Sylvain

Margaux Luck

Heloise Cardinal

Andrea Lodi

2021-01-01

SPACA (published)

proceedings.mlr.press

Multi-Domain Balanced Sampling Improves Out-of-Generalization of Chest X-ray Pathology Prediction Models

Enoch Amoatey Tetteh

Joseph D Viviano

David Scott Krueger

Learning models that generalize under different distribution shifts in medical imaging has been a long-standing research challenge. There ha… (see more)ve been several proposals for efﬁcient and robust visual representation learning among vision research practitioners, especially in the sensitive and critical biomedical domain. In this paper, we propose an idea for out-of-distribution generalization of chest X-ray pathologies that uses a simple balanced batch sampling technique. We observed that balanced sampling between the multiple training datasets improves the performance over baseline models trained without balancing. Code for this work is available on Github. 1

Saliency is a Possible Red Herring When Diagnosing Poor Generalization

Joseph D Viviano

Becks Simpson

Francis Dutil

Poor generalization is one symptom of models that learn to predict target variables using spuriously-correlated image features present only … (see more)in the training distribution instead of the true image features that denote a class. It is often thought that this can be diagnosed visually using attribution (aka saliency) maps. We study if this assumption is correct. In some prediction tasks, such as for medical images, one may have some images with masks drawn by a human expert, indicating a region of the image containing relevant information to make the prediction. We study multiple methods that take advantage of such auxiliary labels, by training networks to ignore distracting features which may be found outside of the region of interest. This mask information is only used during training and has an impact on generalization accuracy depending on the severity of the shift between the training and test distributions. Surprisingly, while these methods improve generalization performance in the presence of a covariate shift, there is no strong correspondence between the correction of attribution towards the features a human expert have labelled as important and generalization performance. These results suggest that the root cause of poor generalization may not always be spatially defined, and raise questions about the utility of masks as 'attribution priors' as well as saliency maps for explainable predictions.

2021-01-01

ICLR (published)

openreview.net

DiVA: Diverse Visual Feature Aggregation for Deep Metric Learning

Timo Milbich

Samarth Sinha

Björn Ommer

2020-11-07

Computer Vision – ECCV 2020 (published)

arxiv.org

Predicting COVID-19 Pneumonia Severity on Chest X-ray With Deep Learning

Beiyi Shen

Almas F Abbasi

Hoshmand Kochi Mahsa

Marzyeh Ghassemi

Haifang Li

Tim Q Duong

Introduction The need to streamline patient management for coronavirus disease-19 (COVID-19) has become more pressing than ever. Chest X-ray… (see more)s (CXRs) provide a non-invasive (potentially bedside) tool to monitor the progression of the disease. In this study, we present a severity score prediction model for COVID-19 pneumonia for frontal chest X-ray images. Such a tool can gauge the severity of COVID-19 lung infections (and pneumonia in general) that can be used for escalation or de-escalation of care as well as monitoring treatment efficacy, especially in the ICU. Methods Images from a public COVID-19 database were scored retrospectively by three blinded experts in terms of the extent of lung involvement as well as the degree of opacity. A neural network model that was pre-trained on large (non-COVID-19) chest X-ray datasets is used to construct features for COVID-19 images which are predictive for our task. Results This study finds that training a regression model on a subset of the outputs from this pre-trained chest X-ray model predicts our geographic extent score (range 0-8) with 1.14 mean absolute error (MAE) and our lung opacity score (range 0-6) with 0.78 MAE. Conclusions These results indicate that our model’s ability to gauge the severity of COVID-19 lung infections could be used for escalation or de-escalation of care as well as monitoring treatment efficacy, especially in the ICU. To enable follow up work, we make our code, labels, and data available online.

2020-07-28

Cureus (published)