January ABC Seminar: Stephen Pfohl, PhD – Google Research – “Algorithmic fairness and responsible AI for health equity”

January ABC Seminar: Stephen Pfohl, PhD – Google Research – “Algorithmic fairness and responsible AI for health equity”

Posted on by Tarissa Arnold Mages

Stephen PfohlIn this talk, I aim to present insights into the design of evaluations of machine learning and AI systems to assess properties related to algorithmic fairness and health equity. I argue that such evaluations are contextual and require specification of the intended use, target population, and assumptions regarding the data generating process and measurement mechanism. Through examples from my research, I argue that causal graphical models can serve as key tools for context specification and can aid in understanding and appropriate use of analytical algorithmic fairness techniques. I will further discuss recent work related to evaluation of equity-related biases in large language models.

Speaker:  Stephen Pfohl, PhD
Affiliation: Google Research
Position:  Senior Research Scientist
Host: Anurag Vaidya, Mahmood Lab

Date: Monday January 27, 2025
Time: 4:00-5:00PM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Research Links: Personal site, Google Scholar

Stephen Pfohl is a senior research scientist at Google Research. His work focuses on the incorporation of fairness, distribution shift, and equity considerations into the design and evaluation of machine learning systems in healthcare contexts. Stephen earned his PhD in Biomedical Informatics from Stanford University.

November ABC Seminar: Brian Hie, PhD – Stanford University – “Sequence modeling from molecular to genome scale with Evo”

November ABC Seminar: Brian Hie, PhD – Stanford University – “Sequence modeling from molecular to genome scale with Evo”

Posted on by Tarissa Arnold Mages

The genome is a sequence that encodes the DNA, RNA, and proteins orchestrating an organism’s function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report the first scaling laws on DNA to complement observations in language and vision. Evo generalizes across DNA, RNA, and proteins, enabling zero-shot function prediction competitive with domain-specific language models and the generation of functional CRISPR-Cas and transposon systems, representing the first examples of protein-RNA and protein-DNA co-design with a language model. Evo also learns how small mutations affect whole-organism fitness and generates megabase-scale sequences with plausible genomic architecture. These prediction and generation capabilities span molecular to genome scales of complexity, advancing our understanding and control of biology.

Title: Sequence modeling from molecular to genome scale with Evo
Speaker:  Brian Hie, PhD
Affiliation: Stanford University, Chemical Engineering and Data Science
Position:  Assistant Professor
Host: Jiening Zhu, PhD – Gerber Lab

Date: Monday November 18, 2024
Time: 4:00-5:00PM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Brian Hie is an Assistant Professor of Chemical Engineering at Stanford University, the Dieter Schwarz Foundation Stanford Data Science Faculty Fellow, and an Innovation Investigator at Arc Institute, where his group conducts research at the intersection of biology and machine learning.

Click here to be added to our mail list.

ABC Hybrid Seminar: Bokai Zhu, PhD – Ragon Institute – “Integration of spatial-omics and single-cell data across modalities with weakly linked features”

ABC Hybrid Seminar: Bokai Zhu, PhD – Ragon Institute – “Integration of spatial-omics and single-cell data across modalities with weakly linked features”

Posted on by Tarissa Arnold Mages

Bokai ZhuAdvancements in single-cell and spatial-omics technologies have created a need for integrating datasets across modalities with limited and weakly correlated features, such as those between spatial proteomics and transcriptomics. Existing tools, usually designed for strongly linked data, often fail in these scenarios. Recently, we have developed a series of methods (Mario and MaxFuse), that improves integration by refining weak correlations between modalities through an iterative smoothing and co-embedding process, and achieves single-cell level matching across these weakly linked modalities, enabling in-depth understanding of tissue micro-environments.

Speaker:  Bokai Zhu, PhD
Affiliation: Ragon Institute of MGH, Harvard and MIT, Broad Institute, MIT
Position:  Postdoctoral Research Fellow
Research Links: https://bokaizhu.github.io/
Host: Muhammad Shaban, PhD – Mahmood Lab

Date: Monday, September 23, 2024
Time: 1:00-2:00PM ET
In-person: Duncan Reid Conference Room (directions below)
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Bokai Zhu is currently a postdoctoral researcher supervised by Prof. Alex Shalek at the Ragon Institute at MGH, MIT, and Harvard. Prior to that, Dr. Zhu obtained his PhD in Microbiology and Immunology from Stanford University, under the supervision of Prof. Garry Nolan. He received a bachelor’s degree in Biology from Cornell University and Zhejiang University. Dr. Zhu’s doctoral research focused on: 1) Experimental assay development for multiplex imaging platforms; 2) Computational algorithm development for single-cell multi-omic integrations; 3)Application of the above tools in various biological systems.

Click here to be added to our mail list.

ABC Seminar: Brian Hie, PhD – Stanford University – “Sequence modeling from molecular to genome scale with Evo”

Title: Sequence modeling from molecular to genome scale with Evo
Speaker:  Brian Hie, PhD
Affiliation: Stanford University, Chemical Engineering and Data Science
Position:  Assistant Professor
Host: Jiening Zhu, PhD – Gerber Lab

Date: Monday November 18, 2024
Time: 4:00-5:00PM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Abstract: The genome is a sequence that encodes the DNA, RNA, and proteins orchestrating an organism’s function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report the first scaling laws on DNA to complement observations in language and vision. Evo generalizes across DNA, RNA, and proteins, enabling zero-shot function prediction competitive with domain-specific language models and the generation of functional CRISPR-Cas and transposon systems, representing the first examples of protein-RNA and protein-DNA co-design with a language model. Evo also learns how small mutations affect whole-organism fitness and generates megabase-scale sequences with plausible genomic architecture. These prediction and generation capabilities span molecular to genome scales of complexity, advancing our understanding and control of biology.

Brian Hie is an Assistant Professor of Chemical Engineering at Stanford University, the Dieter Schwarz Foundation Stanford Data Science Faculty Fellow, and an Innovation Investigator at Arc Institute, where his group conducts research at the intersection of biology and machine learning.

Click here to be added to our mail list.

ABC Hybrid Seminar: Bokai Zhu, PhD – Ragon Institute – “Integration of spatial-omics and single-cell data across modalities with weakly linked features”

Bokai Zhu
Speaker:  Bokai Zhu, PhD
Affiliation: Ragon Institute of MGH, Harvard and MIT, Broad Institute, MIT
Position:  Postdoctoral Research Fellow
Host: Muhammad Shaban, PhD – Mahmood Lab

Date: Monday September 23, 2024
Time: 1:00-2:00PM ET
In person: Duncan Reid Conference Room (directions below)
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Abstract: Advancements in single-cell and spatial-omics technologies have created a need for integrating datasets across modalities with limited and weakly correlated features, such as those between spatial proteomics and transcriptomics. Existing tools, usually designed for strongly linked data, often fail in these scenarios. Recently, we have developed a series of methods (Mario and MaxFuse), that improves integration by refining weak correlations between modalities through an iterative smoothing and co-embedding process, and achieves single-cell level matching across these weakly linked modalities, enabling in-depth understanding of tissue micro-environments.

Research Links: https://bokaizhu.github.io/

Bokai Zhu is currently a postdoctoral researcher supervised by Prof. Alex Shalek at the Ragon Institute at MGH, MIT, and Harvard. Prior to that, Dr. Zhu obtained his PhD in Microbiology and Immunology from Stanford University, under the supervision of Prof. Garry Nolan. He received a bachelor’s degree in Biology from Cornell University and Zhejiang University. Dr. Zhu’s doctoral research focused on: 1) Experimental assay development for multiplex imaging platforms; 2) Computational algorithm development for single-cell multi-omic integrations; 3)Application of the above tools in various biological systems.

Click here to be added to our mail list.

Directions: Duncan Reid Conference Room is located in ASB-1 2nd Floor
When entering the hospital from the main entrance, 75 Francis Street
– Follow the lobby around to the right and take large staircase in front of you to the 2nd floor, then take a left at top of stairs
– When on the main Pike, take the next right at corridor (across from children’s hospital bridge), and a right past the (K) elevators, door straight ahead(Rm #A1020)

February ABC Seminar: Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

February ABC Seminar: Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Posted on by Tarissa Arnold Mages

Cell identity drives cell-cell communication and tissue architecture and is in return regulated by cell-extrinsic cues. Cell identity is determined by the combination of intrinsic developmentally established transcription factor use (TF) and constitutive as well as cell communication-dependent TF activities. Presented work shows two probabilistic models that we developed to advance the understanding of these processes using single-cell and spatial genomic data.

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present cell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assess cell2location in three different tissues and demonstrate improved mapping of fine-grained cell types. In the mouse brain, we discover fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially map a rare pre-germinal center B cell population. In the human gut, we resolve fine immune cell populations in lymphoid follicles. Collectively our results present cell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner.

Python package is provided here:  https://github.com/BayraktarLab/cell2location.

Cell identity and plasticity is regulated by a combinatorial code mediated by transcription factors and the cell communication environment. Systematically dissecting how the regulatory code robustly defines the vast complexity of cell populations across tissues is a long-standing challenge. Measured using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), DNA accessibility provides a readout of intermediate gene regulation steps at single-cell resolution, with technologies measuring both RNA and ATAC providing the necessary evidence to build mechanistic models of regulation. Existing methods address one or several subproblems of modelling DNA accessibility. For example, the DNA sequence-based deep learning models represent combinatorial interactions and in-vivo TF-DNA recognition preferences. In contrast, GRN models use TF abundance profiles across cells and in-vitro-derived TF-DNA recognition preferences, optionally incorporating ATAC-seq data as a filter. All models learn cell-type specific weights and properties and don’t generalize to new TF abundance states such as new cell types. Therefore, we are missing an end-to-end mechanistic model that represents all steps of the biological process, that generalizes to both new DNA sequences and TF abundance combinations and can simultaneously characterize hundreds to thousands of cell states observed in single-cell genomics atlases. Here, we formulated cell2state, a mechanistic end-to-end probabilistic model of TF recruitment to a chromatin locus and downstream TF effect on DNA accessibility. Cell2state is designed to achieve the generalization of regulatory predictions to unseen cell types. Cell2state A) estimates TF nuclear protein abundance and models B) how TFs recognize DNA, C) how TF sites in DNA lead to TF recruitment to a chromatin locus, D) how the activity of DNA-associated TFs affects chromatin accessibility. To evaluate generalization, we defined the computational problem and developed a workflow for predicting the scATAC-seq readout for previously unseen chromosomes and cell types. We show that cell2state outperforms the state-of-the-art deep learning models (ChromDragoNN) at explaining DNA accessibility differences across cells. Finally, to look at cell state plasticity, we developed ways to use cell2state to simulate the possible chromatin states given TF abundance of source cell types.

Speaker:  Vitalii Kleshchevnikov, PhD
Affiliation:  Wellcome Sanger Institute
Position:  Bioinformatician @ Bayraktar, Stegle, Teichmann group
Host: Daniel MacDonald, Gibson Lab

Date: Monday February 26, 2024
Time: 10:00AM-11:00AM ET
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866

Vitalii Kleshchevnikov is driven by a deep interest in three key areas: i) understanding the regulatory code which allows a single genome to specify the full diversity of cell populations and their interaction, ii) formalizing the biology of these processes into mechanistic AI/ML models, and iii) accelerating the therapy development to address ageing alterations in these processes. Vitalii did his PhD jointly supervised by Dr Omer Bayraktar, Dr Oliver Stegle, Dr Sarah Teichmann at Wellcome Sanger Institute (2018-2023) and will present the published and ongoing work. Prior to PhD, Vitalii worked on the role of peptide motifs (SLiMs) in intracellular signaling (Dr Evangelia Petsalaki, EMBL-EBI), predicting CRISR KO mutational outcomes (Dr Leopold Parts, Wellcome Sanger Institute) and profiling protein interactions in accelerated ageing (A*STAR) – while completing MSc and BSc in Kyiv, Ukraine.

Click here to be added to our mail list.

December ABC Seminar: Miriam Adler, PhD – Hebrew University

December ABC Seminar: Miriam Adler, PhD – Hebrew University

Posted on by Tarissa Arnold Mages

Fibrosis is a pathology of excessive scarring which causes morbidity and mortality worldwide. Fibrosis is a complex process involving thousands of factors, therefore, to better understand fibrosis and develop new therapeutic approaches, it is necessary to simplify and clarify the underlying concepts. In this talk, I will introduce a mathematical model we recently developed for a cell circuit between myofibroblasts and macrophages – the two cell types that produce and remodel the scar. The mathematical framework predicts two types of fibrosis – hot fibrosis with abundant macrophages and myofibroblasts, and cold fibrosis dominated by myofibroblasts alone. Moreover, we use the model to predict that the autocrine signal for myofibroblast division is a potential therapeutic target to reduce fibrosis. Finally, I will discuss how we use myocardial infarction (MI), a widely studied in-vivo injury model for cardiac fibrosis, to test these theoretical concepts and intervention strategies experimentally.

Speaker: Miriam Adler, PhD
Speaker Affiliation: Alexander Silberman Institute of Life Sciences and the Faculty of Medicine, Hebrew University of Jerusalem
Speaker Position: Senior Lecturer

Date: Monday  December 18, 2023
Time:  10:00am-11:00am ET **New Time**
Zoom: https://partners.zoom.us/j/82163676866
Meeting ID: 821 6367 6866
Hosted by: Utkarsh Sharma, PhD, Gibson Lab

Research Links: https://adlermiri.wixsite.com/mysite
Google Scholar

Miri Adler completed a BSc in Physics at the Technion and obtained an MSc and a PhD in Physics at the Weizmann Institute with Prof. Uri Alon, studying design principles of biological circuits. In her postdoctoral research working jointly with Prof. Ruslan Medzhitov at Yale University and Prof. Aviv Regev at the Broad Institute of MIT and Harvard, Miri developed theoretical frameworks to uncover universal principles of the collective behavior of cells at the tissue level. Miri received a Fulbright scholarship, EMBO postdoctoral scholarship, Zuckerman STEM leadership program fellowship, and the Israel National Postdoctoral Award Program for Advancing Women in Science. Currently she is an associate research scientist at the Tananbaum Center for Theoretical and Analytical Human Biology at Yale University. As of December, she will be a senior lecturer at the Alexander Silberman Institute of Life Sciences and the Faculty of Medicine at the Hebrew University of Jerusalem.

Click here to be added to our mail list.

November ABC Seminar: Gennady Gorin, PhD – CalTech

November ABC Seminar: Gennady Gorin, PhD – CalTech

Posted on by Tarissa Arnold Mages

Stochastic foundations for single-cell RNA sequencing

Single-cell RNA sequencing, which quantifies cell transcriptomes, has seen widespread adoption, accompanied by a proliferation of analytic methods. However, there has been relatively little systematic investigation of its best practices and their underlying assumptions, leading to challenges and discrepancies in analysis. I motivate a set of generic, principled strategies for modeling the biological and technical stochasticity in sequencing experiments, and use case studies to illustrate their prospects for the discovery and interpretation of biophysical kinetics.

Research links:

 

Dr. Gennady Gorin is a chemical engineer working at the exciting intersection of bioinformatics, stochastic biophysics, and statistics. He completed his Ph.D. with Lior Pachter at the California Institute of Technology, adapting theory from fluorescence transcriptomics to the unique features of single-cell RNA sequencing. Prior, he completed a B.S./B.A. at Rice University and performed transcriptional modeling research in the Golding laboratory at Baylor College of Medicine. Gennady is transitioning to industrial bioinformatics, and excited about the prospects for rigorous, physics-informed methods in method development.

All Welcome! Note this event will take place on Zoom.

Date: Monday November 20, 2023
Time: 4:00-5:00PM

Click here to be added to our mail list.

For further information about this seminar series, contact tarnoldmages@bwh.harvard.edu

October ABC Seminar: Weiruo Zhang, PhD, Stanford University

October ABC Seminar: Weiruo Zhang, PhD, Stanford University

Posted on by Tarissa Arnold Mages

Spatial biology is a new frontier that has become accessible through advances in spatial profiling technologies, such as multiplexed in situ imaging spatial proteomics, which can provide single-cell resolution up to 60 markers. In this talk, I will introduce a computational analysis pipeline that performs integrative analysis of spatial proteomics and single-cell RNA sequencing to identify clinically-relevant cellular interactions. The pipeline features (1) CELESTA, an unsupervised machine learning method for cell type identification in multiplexed spatial proteomics data; (2) a geospatial statistical method to identify cell-cell colocalizations; and (3) an integrative coupling of spatial proteomics and single-cell RNA sequencing data that identified cell-cell crosstalk associated with lymph node metastasis in head and neck cancer which we have validated through mouse model studies.

Research link:
https://profiles.stanford.edu/weiruo-zhang

Dr. Zhang is currently a Research Engineer at the Department of Biomedical Data Science and the Center for Cancer Systems Biology, Stanford School of Medicine. Dr. Zhang received her M.S. and Ph.D. in Electrical Engineering, both from Stanford University, with a focus on bioinformatics and developing computational algorithms for metabolomics data analysis. Her current research at Stanford primarily focuses on developing and implementing computational methods to integrate and analyze single-cell and spatial multi-omics data, such as single-cell RNA sequencing, spatial proteomics and spatial transcriptomics. Her research aims to apply quantitative approaches that bridge multi-omics, imaging, machine learning, and artificial intelligence to decipher biology for cancer progression and guide treatment responses.

 

Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Vitalii Kleshchevnikov, PhD – Wellcome Sanger Institute – “Probabilistic models to resolve cell identity and tissue architecture”

Speaker:  Vitalii Kleshchevnikov, PhD
Affiliation:  Wellcome Sanger Institute
Position:  Bioinformatician @ Bayraktar, Stegle, Teichmann group
Host: Daniel MacDonald, Gibson Lab

Abstract:  Cell identity drives cell-cell communication and tissue architecture and is in return regulated by cell-extrinsic cues. Cell identity is determined by the combination of intrinsic developmentally established transcription factor use (TF) and constitutive as well as cell communication-dependent TF activities. Presented work shows two probabilistic models that we developed to advance the understanding of these processes using single-cell and spatial genomic data.

Spatial transcriptomic technologies promise to resolve cellular wiring diagrams of tissues in health and disease, but comprehensive mapping of cell types in situ remains a challenge. Here we present cell2location, a Bayesian model that can resolve fine-grained cell types in spatial transcriptomic data and create comprehensive cellular maps of diverse tissues. Cell2location accounts for technical sources of variation and borrows statistical strength across locations, thereby enabling the integration of single cell and spatial transcriptomics with higher sensitivity and resolution than existing tools. We assess cell2location in three different tissues and demonstrate improved mapping of fine-grained cell types. In the mouse brain, we discover fine regional astrocyte subtypes across the thalamus and hypothalamus. In the human lymph node, we spatially map a rare pre-germinal centre B cell population. In the human gut, we resolve fine immune cell populations in lymphoid follicles. Collectively our results present cell2location as a versatile analysis tool for mapping tissue architectures in a comprehensive manner.

Python package is provided here:  https://github.com/BayraktarLab/cell2location.

Cell identity and plasticity is regulated by a combinatorial code mediated by transcription factors and the cell communication environment. Systematically dissecting how the regulatory code robustly defines the vast complexity of cell populations across tissues is a long-standing challenge. Measured using the assay for transposase-accessible chromatin with sequencing (ATAC-seq), DNA accessibility provides a readout of intermediate gene regulation steps at single-cell resolution, with technologies measuring both RNA and ATAC providing the necessary evidence to build mechanistic models of regulation. Existing methods address one or several subproblems of modelling DNA accessibility. For example, the DNA sequence-based deep learning models represent combinatorial interactions and in-vivo TF-DNA recognition preferences. In contrast, GRN models use TF abundance profiles across cells and in-vitro-derived TF-DNA recognition preferences, optionally incorporating ATAC-seq data as a filter. All models learn cell-type specific weights and properties and don’t generalize to new TF abundance states such as new cell types. Therefore, we are missing an end-to-end mechanistic model that represents all steps of the biological process, that generalizes to both new DNA sequences and TF abundance combinations and can simultaneously characterize hundreds to thousands of cell states observed in single-cell genomics atlases. Here, we formulated cell2state, a mechanistic end-to-end probabilistic model of TF recruitment to a chromatin locus and downstream TF effect on DNA accessibility. Cell2state is designed to achieve the generalization of regulatory predictions to unseen cell types. Cell2state A) estimates TF nuclear protein abundance and models B) how TFs recognize DNA, C) how TF sites in DNA lead to TF recruitment to a chromatin locus, D) how the activity of DNA-associated TFs affects chromatin accessibility. To evaluate generalization, we defined the computational problem and developed a workflow for predicting the scATAC-seq readout for previously unseen chromosomes and cell types. We show that cell2state outperforms the state-of-the-art deep learning models (ChromDragoNN) at explaining DNA accessibility differences across cells. Finally, to look at cell state plasticity, we developed ways to use cell2state to simulate the possible chromatin states given TF abundance of source cell types.

Vitalii Kleshchevnikov is driven by a deep interest in three key areas: i) understanding the regulatory code which allows a single genome to specify the full diversity of cell populations and their interaction, ii) formalizing the biology of these processes into mechanistic AI/ML models, and iii) accelerating the therapy development to address ageing alterations in these processes. Vitalii did his PhD jointly supervised by Dr Omer Bayraktar, Dr Oliver Stegle, Dr Sarah Teichmann at Wellcome Sanger Institute (2018-2023) and will present the published and ongoing work. Prior to PhD, Vitalii worked on the role of peptide motifs (SLiMs) in intracellular signaling (Dr Evangelia Petsalaki, EMBL-EBI), predicting CRISR KO mutational outcomes (Dr Leopold Parts, Wellcome Sanger Institute) and profiling protein interactions in accelerated ageing (A*STAR) – while completing MSc and BSc in Kyiv, Ukraine.

Click here to be added to our mail list.