Understanding the causes of disease & Covid 19 – connecting molecular science with health records • Chairs:

• John Danesh, University of Cambridge

• Adam Butterworth, University of Cambridge

• Panellists:

• Ewan Harrison, University of Cambridge

• Mark Caulfield, Queen Mary University of London

• Aroon Hingorani, UCL

• Emily Jefferson, University of Dundee

This session will start at 11:45 BST.Please use the Q&A function to ask questions to speakers. You are welcome to comment using the chat function, but we cannot guarantee this will be monitored.

Understanding Causes of Diseases:Linking molecular science to e-Health Records at scale

Integrative

analyses

Multi-omics

cohorts

Empowering

genomic

medicine

Building

tools &

resources

• Multi-omics Cohorts Consortium

• Microbial carriage

• ‘Gut Reaction’ Health Data Research Hub

• Genomic medicine for rare diseases

• Polygenic Score Catalog

• Addressing ethnicbias in genomic medicine

25/06/2020

Tracking SARS-CoV-2 in the UK

Ewan Harrison

https://www.cogconsortium.uk

COVID-19 GENOMICS UK (COG-UK) consortium

15 regional sites:

1. Belfast

2. Birmingham

3. Cardiff (PHW)

4. Cambridge

5. Edinburgh

6. Exeter

7. Glasgow

8. Liverpool

9. Newcastle

10. Nottingham

11. Oxford

12. Portsmouth

13. London (UCL)

14. London (PHE – Colindale)

15. Sheffield

Central sequencing site

and COG-UK Hub

COG-UK Administration

£20M

Operational structure

Regional

sequencing sites

Electronic health records

UK Public Health Agencies

COG-UK Analysis teams UK Public Health Agencies

COG-UK

Sequencing hub

Laboratories

Laboratories

Sequencing

https://www.ncbi.nlm.nih.gov/books/NBK554776/figure/article-52171.image.f5/

Sequencing technology agnostic

Open access data

COG-UK - Analytical focus

• Introductions and spread

• Nosocomial transmission

• Tracking variation – diagnostics primer binding sites

• Treatments and vaccines – following the emergence of drug resistance and

variation in vaccine antigens

• Transmission tracking – effects of interventions, outbreaks, contact tracing

• Evolutionary analysis

• Tracking emergence of viral variants

Ongoing analysis

• Determined numbers of introductions and likely source

• Emergence of three dominant lineages UK5, UK16 and UK17.

• Estimation of R in London

• Hospital and care home transmissions

• Screening of diagnostic primers

• Effect of D614G spike proteins mutation

Andrew Rambaut

Oliver Pybus

Nick Loman

Tom Connor

Richard Myers

David Aanensen

Erik Volz

Host

Genomics and clinical data

linkage

International

Analysis and knowledge exchange

4

of both some transmission within the UK and multiple introductions of the same lineage (i.e. from a

common holiday destination visited by individuals from across the UK).

Focusing on London (Figure 3), a notable number of lineages

are or have been in circulation and identified in the genome

sequences sampled to date. Incorporation of postcode and

other epidemiological data will enable the within-city patterns

of transmission and spread to be assessed.

It should be noted that there is no current evidence of different

lineages being associated with any distinct biological or

clinical characteristics (e.g. transmissibility, disease severity,

drug resistance).

With the framework established for systematic genomic

surveillance of most of the UK, we can begin to look for

changing patterns in transmission of viral lineages. For

example, can we detect a shift from diverse imports to more

homogenous geographical lineages circulating in the UK?

Local reporting

feeding back to NHS

National infrastructure

Second COVID-19 wave

Future pandemics – flu

Future

COG-UK author listDavid M Aanensen1,2, Khalil Abudahab1,2, Alexander Adams3, Safiah Afifi4, Mohammed T Alam5, Alex Alderton6, Nabil-Fareed Alikhan7, John Allan8, Mai Almsaud9, Abdulrahman Alrezaihi9, Muhannad Alruwaili9, Roberto Amato6, Monique

Andersson10, Adrienn Angyal11, Elihu Aranday-Cortes12, Cristina Ariani6, Stuart D Armstrong9, Patawee Asamaphan12, Stephen Attwood13, Alp Aydin7, Anjna Badhan14, David Baker7, Paul Baker15, Carlos E Balcazar16, Jonathan Ball17,

Edward Barton18, Matthew Bashton8, Laura Baxter5, Matthew Beale6, Charlotte Beaver6, Angela Beckett19, Rob Beer4, Andrew Beggs20, Andrew Bell7, Katie Bellis6,21, Eleanor G Bentley9, Matt Berriman6, Emma Betteridge6, David Bibby22,

Kelly Bicknell23, Alec Birchley3, Gary Black8, Beth Blane21, Samuel Bloomfield7, Frankie Bolt24,25, David G Bonsall26, Andrew Bosworth22, Yann Bourgeois27, Olivia Boyd28, Daniel Bradshaw22, Judy Breuer29, Hannah Bridgewater5, Tony

Brooks29, Julianne R Brown30, Rebecca L Brown11, Kirstyn Brunker12, Giselda Bucca31, David Buck26, Matthew Bull3, Ethan Butcher23, Sarah L Caddy32, Laura G Caller33, Sharon Cambell34, Matthew Carlile35, Stephen Carmichael12, Laura

Carrilero11, Sergi Castellano29, Jennifer Chaloner36, Meera Chand22, Michael R Chapman6,21,37, Joseph Chappell17, Anoop J Chauhan23, Anu Chawla38, Jeff Cheng5, Carol M Churcher21, Gemma Clark39, Jordan J Clark9, Jennifer Collins40,

Rachel Colquhoun16, Thomas R Connor3,41, Chrystala Constantinidou5, Jason Coombes3, Sally Corden3, Simon Cottrell3, Angela Cowell38, Martin D Curran22,42, Tanya Curran43,44, Gavin Dabrera22, John Danesh6, Alistair C Darby9,

Mariateresa de Cesare26, Leonardo de Oliveira Martins7, Thushan I de Silva11, Bisrat Debebe35, Samir Dervisevic45, Rebecca A Dewar16,46, Maria Diaz7, Matthew Dorman6, Gordon Dougan47, Lynn Dover8, Fatima Downing3, Eleanor Drury6,

Louis du Plessis13, Patricia L Dyal29, Richard Eccles9, Sue Edwards3, Nicholas Ellaby22, Scott Elliott23, Gary Eltringham40, Ngozi Elumogo45, Sarah Essex15, Cariad M Evans48, Johnathan Evans3, Fabricia F. Nascimento28, Derek J

Fairley43,44, Ben Farr6, Theresa Feltwell47, Neil Ferguson28, Ana da Silva Filipe12, Jacqueline Findlay29, Leysa M Forrest29, Sally Forrest21, Luke Foulser6, Sarah Francois13, Lucy Frost5, Eileen Gallagher22, Michael D Gallagher16, Isabel

García-Dorival9, Amy Gaskin3, Bree Gatica-Wilcox3, Artemis Gavriil29, Lily Geidelberg28, Matthew Gemmell9, Alessandro Gerada38, Lauren Gilbert3, Paul Gilmore9, Rachel Gilroy7, Sophia Girgis21, Sharon Glaysher23, Tanya Golubchik26,

Sonia Goncalves6, Ian Goodfellow33, Scott Goodwin6, Clive Graham18, Lee Graham3, Dimitris Grammatopoulos20, Angie Green26, Luke R Green11, Jane Greenaway15, Richard Gregory9, Danielle C Groves11, Natalie Groves22, Martyn

Guest41, Rory Gunson49, Sam Haldenby9, Grant Hall33, William L Hamilton50, Ximeng Han9, Kathryn A Harris30, Ewan M Harrison6,21, Catherine Hartley9, Carolina Herrera51, Andrew Hesketh31, David Heyburn3, Verity Hill16, Julian Hiscox9,

Alison Holmes24,25, Nadine Holmes35, Giles S Holt52, Myra Hosmillo33, Charlotte J Houldcroft47, Jonathan Hubb22, Joseph Hughes12, Margaret Hughes9, Robert Impey23, Miren Iturriza-Gomara9, Adam Jackson6, Ben Jackson16, David K

Jackson6, Aminu S Jahun33, Keith James6, Dorota Jamrozy6, Aaron Jeffries53, Natasha Jesudason12, Michaela John4, James Johnson9, Katie J Johnson48, Natasha Johnson12, Ian Johnston6, Benjamin Jones9, Rachel Jones3, Sophie

Jones3, David Jorgensen28, Leanne Kane6, Gemma Kay7, Sally Kay6, Jon-Paul Keatley6, Alexander J Keeley48, Fahad A Khokhar47, Christine Kitchen41, Bridget Knight54, Anastasia Kolyva7, Moritz Kraemer13, Mark Kristiansen29, Sara

Kumziene-Summerhayes3, Dominic Kwiatkowski2,6, Angie Lackenby22, Cordelia Langford6, Mara Lawniczak6, Thanh Le-Viet7, David Lee22, Laura Letchford6, Kathy Li12, Ling Li24, Steve Liggett15, Benjamin B Lindsey11, Rich Livett6, Allyson

Lloyd23, Stephanie Lo6, Joshua Loh8, Nicholas J Loman55, Matthew Loose35, Anita Lucaci9, Catherine Ludden6, Lisa Luu9, Ronan A Lyons56, George MacIntyre-Cockett26, Alasdair MacLean49, Daniel Mair12, Josh Maksimovic4, Robyn

Manley53, Carmen Manso22, Jenifer Manson38, Inigo Martincorena6, Jane Masoli57, Alison E Mather7, Tamyo Mbisa22, Kathryn McCluggage4, JT McCrone16, Sarah McDonald12, Martin P McHugh16,46,58, James M McKenna43,44, Patrick

Mclure17, Liz McMinn6, Claire McMurray55, Lizzie Meadows7, Mirko Menegazzo1,2, Luke W Meredith33, Ian Merrick41, Lamia Mestek-Boukhibar29, Shahjahan Miah22, Stephen Michell53, Michelle L Michelsen53, Zoltan Molnar44, Catherine

Moore3, Catrin Moore10, Christopher Moore35, Nathan Moore59, Mari Morgan3, Sian Morgan4, Dawn Muddyman1,2, David A Muir24, Richard Myers22, Eleni Nastouli60, Plamena Naydenova21, Andrew Nelson61, Charlotte Nelson9, Rachel

Nelson6, Samuel Nicholls55, Jenna Nichols12, Marc Niebel12, Paola Niola29, Kyriaki Nomikou12, Justin O'Grady7, Áine N O'Toole16, Elaine O’Toole38, Cassie Olateju38, Richard J Orton12, Husam Osman22, Sascha Ott20, Nicole Pacchiarini3,

Debra Padgett18, Andrew J Page7, Sophie Palmer21, Steve Palmer6, Yasmin N Panchbhaya29, Sarojini Pandey5, Naomi Park6, Matthew D Parker11, Julian Parkhill62, Yasmin Parr12, Paul J Parsons11, David G Partridge48, Minal Patel6, Steve

Patterson9, Brendan Payne40, Sharon J Peacock21,22, Rebekah Penrice-Randal9, Malorie Perry3, Steven Platt22, Radoslaw Poplawski55, Reenesh Prakash45, Liam Prestwood6, Anna Price41, James R Price24,25, Christoph Puethe6, Oliver

Pybus13, Mike Quail6, Joshua Quick55, Jayna Raghwani13, Manon Ragonnet-Cronin28, Saadia Rahman29, Lucille Rainbow9, Shavanthi Rajatileka6, Andrew Rambaut16, Mary Ramsay22, Paul A Randell24, Nadine P Randle9, Veena

Raviprakash34, Mohammad Raza48, Paola Resende Silva29, Sara Rey3, Alex Richter20, David L Robertson12, Trevor Ian Robinson38, Samuel C Robson19, Stefan Rooke16, Aileen Rowan14, Will Rowe55, Sunando Roy29, Steven Rudder7,

Chris Ruis21, Fei Sang35, Garry Scarlett27, Ulf Schaefer22, Carol Scott6, Garren Scott18, Rajiv Shah12, Parul Sharma9, Ghada T Shawli9, James Shepherd12, Nicola Sherriff34, Lesley Shirley6, John Sillitoe6, David A Simpson44, Josh Singer12,

Igor Siveroni28, Christen Smith6, Colin P Smith31, Darren L Smith61, Nikki Smith11, Wendy Smith39, Kathy Smollett12, Joel Southgate3,41, Karla Spellman4, Michael Spencer-Chapman6, Sushmita Sridhar21, Rachael Stanley45, Richard Stark5,

James P Stewart9, Joanne Stockton55, Claire Stuart45, David Studholme53, Neil Swainston9, Emma Swindells63, Mohammad A Tariq64, Ben Taylor1,2, Graham P Taylor14, Sarah Taylor3, Grace Taylor-Joyce5, Ana P Tedim7, Ben Temperton53,

Kate E Templeton16,46, Emma C Thomson12, Nicholas M Thomson7, Alicia Thornton22, Scott Thurston6, John Todd26, Lily Tong12, Gerry Tonkin-Hill6, M. Estée Török47, Amy Trebes26, Alexander J Trotter7, Theocharis Tsoleridis17, Rachel M

Tucker11, Helena J Tutill29, Anthony Underwood1,2, Meera Unnikrishnan5, Ecaterina Vamos9, Tetyana Vasylyeva13, Sreenu Vattipally12, Erik M Volz28, John Wain7, Dennis Wang11, Joanna Warwick-Dugdale53, Elizabeth Wastnedge46, Joanne

Watkins3, Joanne Watts38, Mark Webber7, Sam Weeks29, Danni Weldon6, Mark Whitehead9, Charlotte A Williams29, Chris Williams3, David Williams22, Rachel Williams29, Thomas C Williams16,46, Emma Wise59, Victoria Wright35, Matthew D

Wyles11, Sarah Wyllie23, Anna Yakovleva33, Muhammad Yasir7, Corin Yeats1,2, Wen C Yew8, Greg R Young8, Xiaoyu Yu16, Alex Zarebski13

The GenOMICC – Genomics England - CoG-UK partnership

Co-Leads: Kenneth Baille, Sharon Peacock, Sue Hill, Andrew Morris, Mark Caulfield

Whole genome sequencing of patients severely affected by COVID-19

Severely ill patients with proven COVID-19

Genomics England Dataset UK Biobank Dataset

Prospective COVID-19 Retrospective Study and Case Controls

Key core clinical datasetLongitudinal life-course

follow-upViral genome (PHE)

Human whole genome sequence of up to 20,000

severely ill patients

WGS of 97,000 participants627 families with primary

immunodeficiencyLongitudinal life-course

follow-up

Immunodeficiency variant analysisViral infections research GeCIP

Case control analysis

500,000 participants, 40-69 years with exomes available during 2020 (50K WGS soon)

Longitudinal life-course follow-up

Case control analysis

Outputs

Host vs. viral genomic architecture and susceptibility

Identification of new host genomic variants

Polygenic risk scores for flu-virus susceptibility

Dat

aA

nal

ysis

Co

ho

rt Mildly affected patients with proven COVID-19

Key core clinical datasetLongitudinal life-course

follow-upViral genome (PHE)

Human whole genome sequence of up to 15,000 mildly affected patients

Extreme case : mild control analysis

Polygenic risk scores for flu-virus susceptibility

Power: Severe versus mildly affected offers 80% power to detect genome-wide significance at low (~1.1) relative risk at 20% risk allele frequency

The Team

• GenOMICC

• Genomics England

• NHS England

• NHS Staff @13 Genomic Medicine Centres,

• 7 Genomic Lab Hubs,

• Ireland, Scotland, Wales

• 3000 plus researchers worldwide

• France Genomique, Qatar, Canada,

• Illumina

1325 June 2020

How multi-omic cohorts are being used to study risk factors for COVID-19

Dr Adam ButterworthUniversity of Cambridge

16th June 2020

Why is it informative to use existing population cohorts to study COVID-19?

• Extensive data, including clinical, genetic and multi-omics data, has already been recorded

• Avoids potential distortion of measurements due to the acute phase of disease

• Prospective design avoids reverse causation

• Minimises biases arising from trying to find matched non-COVID-19 controls

→ Valuable insights should be gained from studying existing population cohorts as well as patient collections

Each with: genomic data, EHR linkages and multi-omics data

HDRUK multi-omics consortium: ~a dozen cohorts with ~800K participants

Identify molecular factors associated with risk of COVID-19, severity, complications etc

Assess causality to inform understanding of COVID-19

Build and test predictive models

Inform therapeutic strategies

Threats / challenges to robust insights?

1) Statistical power – potential solutions: scale up the National Multi-omics Consortium, collaborate (both nationally and internationally, e.g. COVID-19 Host Genetics Initiative, SCALLOP)

2) Availability of relevant linked COVID-19 data – potential solutions: share initial learning, work together to streamline effort, support data providers

3) Methodological biases – potential solutions: work closely with methodologists to understand and minimise potential biases, careful phenotype definitions and comparisons

4) Computational infrastructure – potential solutions: federated analytical approaches, harness COVID-19 opportunity to accelerate development and uptake of suitable TREs

Implications of using multi-omiccohorts for medicines development

Professor Aroon Hingorani

𝛼 =probability of transmission𝐶= number of daily contacts𝐷= infection duration (days)𝑅= 𝛼* 𝐶* 𝐷

Viral protein

Host protein

Entry + +

Replication + +

Host response +

Public health Vaccine Medicines

Natural genetic variation

transcriptome

proteome

metabolome

physiome radiome

diseaseome

exposome

small molecule

large molecule

antisense

Natural genetic variation

transcriptome

proteome

metabolome

physiome radiome

diseaseome

small molecule

large molecule

antisense

Human genomics and drug development

Maik Pietzner, Nick Wareham and Claudia Langenberg et al.In submission

Ellinghaus et al MedRxiv, 2020

Genetic approach to drug target identification and validation for Covid-19

AfterGordon et al., Nature 2020Messner et al. Cell Systems, 2020

Implications of using multi-omiccohorts for infrastructure to enable cross-cohort multi-dimensional analyses

Professor Emily Jefferson

Bridge across 2 Worlds!

World of routinely collected clinical records

World of omicdata (biomolecular data )

Safe Havens have traditionally supported epidemiological research on small data using standard stats packages

→ Big Data?

→ Programming access?

→ Installation of researcher tools?

→ Cost of environment and software?

→ Suitable hardware?

→ Exporting of Algorithms?

Trusted Research Environments (TREs) need to be enhanced to support multi-omic data analysis

Next Generation TREs!