Agenda: The BRAIN Initiative® Cell Atlas Workshop: From Single-Cell Genomics to Brain Function and Disorders—Data Integration and Annotation

Day 1, January 16, 2024

Plenary Session

• Opening Remarks – John Ngai (Director, NIH BRAIN Initiative) (11:30-11:40am)
• Introduction of BRAIN Initiative Cell Atlas Program and the Workshop (Yong Yao, NIH Program Director and Laura Reyes, NIH Program Analyst) (11:40-11:50 a.m.)

Session 1. Brain Cell Atlas Data Analysis, Annotation, and Integration

Maximizing the value of vast single-cell resources requires the development of integrated brain cell atlases to address key questions on the nature and structure of cell types, their variability, and significance. In Session 1, we investigate the requirements and path to the development of complete, accurate, and permanent brain cell atlases. A series of invited topical presentations addressing the following questions will be followed by a panel discussion.

Keynote Presentations

• Whole Mouse Brain Multimodal Atlas (Hongkui Zeng, Allen Institute) (11:50 a.m.-12:10 p.m.)
• Developing Brain Cell Atlases (Aparna Bhaduri, UCLA, Tom Nowakowski, UCSF) (12:10-12:30 p.m.)

Break (12:30-12:50 p.m.)

Panel 1: Brain Cell Atlas Data Integration and Annotation (12:50-2:20 p.m.)

1. Where are we in terms of a common understanding of cell types? What are the operational definitions and assumptions? What can be agreed upon level of granularity for a reference brain cell atlas? What mapping approaches are being done and are useful? What remains to be done to fully leverage the variety of single-cell genomics data?
2. Data Integration and Annotation: (i) Spatial and anatomical mapping: How will spatial information be integrated? Which common coordinate framework (CCF) will be used? (ii) Developmental axis: Consider prenatal and postnatal developmental stages and on a shorter time scale, have responses to perturbations been used to gain granular insight into cellular/circuit biology and taxonomic classes? (iii) Cross-modality: How can the gene co-expression modules and regulatory program be identified? (iv) Cross-species: How can we most effectively develop a shared cell type taxonomy that includes enough different species as experimental paradigms to inform brain biology?
3. Which data tools and models are suitable for large-scale integration and annotation? How will data tools and models be evaluated and benchmarked (pros and cons)?

Keynote Presentation

• An Atlas of Human Brain Cell Variation (Steve McCarroll, Broad Institute) (2:20-2:40 p.m.)

Break (2:40-2:50 p.m.)

Panel 2: Challenges in Human Brain Cell Data Analysis, Integration, and Annotation (2:50-4:20 p.m.)

1. How do we quantify cell and sample variabilities across individual human brain cases and conditions?
2. Which variabilities can be attributed to biological vs technical sources?
3. How many donor cases are needed to characterize the individual variabilities?

Day 1 Wrap-Up and Conclusions (4:20-4:30 p.m.)

Day 2, January 17, 2024

Plenary Session

• Summary and Highlights of Day 1 (11:30 a.m.-12:00 p.m.)

Session 2. Brain Cell Atlas Data, Tools, Knowledge, and Community

Structured data organization, standardization, and powerful tools are essential to maximize the utility of single cell brain atlases. The infrastructure requirements and data ecosystem for delivering brain cell type data and knowledge are substantial and existing tools can benefit for improved integration. A series of invited presentations will address key questions on how data, software tools, and knowledge can be managed and disseminated at scale. This will be followed by software tool demonstrations and panel discussion.

Keynote Presentation

• Genomics Data Commons and Ecosystem (Robert Grossman, University of Chicago) (12:00-12:20 p.m.)
• Organizing Brain Cell Type Data & Knowledge – Opportunities and Challenges (TBD) (12:20-12:40 p.m.)

Break (12:40-1:00 p.m.)

Panel 1. Brain Cell Atlas Data to Knowledge Pipelines (1:00-2:30 p.m.)

1. How will common data processing pipelines facilitate data quality control, analysis, visualization, integration, and annotation at scale across species, developmental stages, and perturbations?
2. What cell annotation and knowledge will be extracted from single-cell genomics data? Which types of queries and searches are developed by brain cell data archives, cell atlas portals, and knowledgebase?
3. How will brain cell atlases and knowledge be versioned and kept up to date?
4. What are ways to collect user experience, user-based annotation and proofreading to enhance the data resource products design?
5. How will the BICAN data archives and knowledgebase link and integrate with other data and knowledge resources generated by the research community?
6. What is the best relationship with cell atlas and disease research consortia? What specific actions should be taken with which consortia?
7. What goals can be set to synergize and mutually benefit projects across the consortia?
8. What organizational framework can facilitate coordination of projects so that investigators can do things beyond individual labs?
9. What types of new projects could be created using brain cell atlases through this framework and collaboration?

Panel 2. Brain Cell Atlas Showcase Demonstrations (2:30-4:00 p.m.)

• Hands-on querying and browsing of brain cell atlases, e.g., Map My Cells.

Plenary Session

• Summary and Highlights of Day 2 - Towards an Analysis and Annotation Data Ecosystem (4:00-4:30 p.m.)

Day 3, January 18, 2024

Session 3. Brain Cell Atlases for Neuroscience in Health and Disorders.

A major value and outcome of brain cell atlases will be in their advancement of research in health and disease. In Session 3, we will address essential considerations for making these data most applicable for translational applications. The session invites topical presentations and discussion on several topics.

Keynote Presentation

• Gene Regulatory Atlas and Cell Type Enhancer Prediction (Joe Ecker, Salk, Bing Ren, UCSD, and Nelson Johansen, Allen Institute) (11:30-11:50 a.m.)

Panel 1. Brain Cell Atlases for Neuroscience Research (11:50 a.m.-1:20 p.m.)

1. Which cell type-specific tools are available and will be generated to monitor and manipulate brain cell activities across species (human, macaque, marmoset, mouse)?
   1. Any emerging tools for wide-scale mapping of neuronal connectivity and synaptic plasticity, high-resolution structural circuit connectivity, and/or neural activity mapping?
   2. How do we most effectively leverage these tools democratically so that work can be done in a community-built way?
   3. How will the data generated by the individual labs be integrated with BICAN reference atlases?
2. What scientific insights can be acquired from single-cell genomics datasets (e.g., gene expression and regulation program, neurotransmission, neuromodulation, neuroimmune and other types of cell-cell communication, synaptic connectivity coding, evolutionary divergence, and convergence)?
3. What are the caveats, challenges and key next steps in interpreting and testing hypotheses generated by these datasets? To what extent can other scalable approaches be applied to further characterize cell type properties?

Break (1:20-1:40 p.m.)

Keynote Presentation

• A Multimodal Brain Cell Atlas and Community Resource of Alzheimer’s Diseases (Ed Lein, Allen Institute) (1:40-2:00 p.m.)

Panel 2. Brain Cell Atlases in Brain Disorder Research (2:00-3:30 p.m.)

1. Which use cases and hypotheses can be developed in studying human brain health and disease conditions?
2. Which brain disease research consortia and labs might synergize with BICAN?
   1. What inclusion and exclusion criteria are used for selecting postmortem brain samples as a control group? Feasibility of sharing ‘neurotypical’ brain samples?
   2. Coordination and collaboration on the development of data standards and data ecosystem to facilitate joint analysis.

Break (3:30-3:40 p.m.)

Plenary Session

• Workshop Summary, Next Steps, and Roadmap (3:40-4:30 p.m.)