WGS as a starting point to understand AMR Jennifer Gardy, Canada Research Chair in Public Health Genomics, University of British Columbia & BC Centre for Disease Control @jennifergardy with Laura Piddock, Professor of Microbiology, University of Birmingham @LauraPiddock
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WGS as a starting point to understand AMR Jennifer Gardy, Canada Research Chair in Public Health Genomics, University of British Columbia & BC Centre for Disease Control @jennifergardy
with Laura Piddock, Professor of Microbiology, University of Birmingham @LauraPiddock
The 37,000 foot view
The 37,000 foot view
PMC4525730PMC4156311
1995-20042005 2014
14,000
12,000
10,000
8,000
6,000
4,000
2,000
0 Adap
ted
from
Land
et al
., PM
C436
1730
There are over 70,000 prokaryotic genomes in NCBI
We sequenced 36 TB genomes!
We sequenced 1400 TB genomes!
WGS is now POC
or point-of-smartphone!
From proof-of-concept to clinical implementation
academic clinical
understand diagnose characterize track
PMC4698465
356 samples, 8 sites
Speciation - 93%
Resistance - 93%
Faster Cheaper
What does WGS mean for AMR: diagnosis?
Clinicians want to know what a bug is and what
to treat it with. Fast.
Is WGS faster than NAATs or LPAs for
diagnosis/speciation? Not really.
1. WGS will impact AMR diagnostics by offering new insights and new targets
PMC3989053
• 2007 S. aureus isolate, phenotypically MRSA but no mecA • WGS at Sanger revealed mecA homolog with 69% identity - named mecC • mecC detected all over the place after its discovery • Diagnostic PCRs and Vitek protocols changed to capture this new gene
What does WGS mean for AMR: resistance prediction?
2. WGS couples diagnosis and resistance prediction
PMC4703848 http://www.mykrobe.com
3. WGS identifies and queries a larger set of resistance determinants
Walker et al, Lancet ID, PMC4579482
3651 Mtb isolates sequenced, 232 resistance determinants found
PMC4295408
PMID 15591164 (OA)
Sequenced 3 isolates after BDQ tx
4. WGS enables the discovery of new antimicrobial mechanisms of action
PMC4556809
PMC4587932
5. WGS reveals the drivers and
evolution of within-host and population-level
evolution of resistance.
What does WGS mean for AMR: transmission & epidemiology?
PMC4203314
6. WGS can reconstruct AMR outbreaks and
inform infection control.
6. WGS can differentiate
between mutational and plasmid-
mediated resistance.PMID: 23543608 (OA)
PMID: 27150362 (OA)
7. WGS can describe the emergence and spread
of AMR lineages.
8. WGS reveals inherent mutational capacityFord et al, Nat Genet, PMC3777616
Roadblocks
DIAGN
OSIS
1. Sensitivity in sequencing from a clinical sample
2. Clinical metagenomics - who’s the pathogen, who’s a commensal, who’s a contaminant?
RESIS
TANC
E PRE
DICTIO
N 1. What’s a resistance-determining mutation versus a compensatory or other mutation?
2. What is the effect of rare variants on resistance phenotype?
3. What’s in the databases? Who is maintaining the databases?
4. How the @#$% are we supposed to identify resistance associated with different modes, levels of gene expression?
5. Are people releasing enough well-annotated genomes to enable comparative genomics efforts?
EPIDE
MIOL
OGY
1. How can we infer transmission from genomic data alone?
2. How can we infer transmission when it’s not just a strain but an MGE that’s moving?
3. Do we have enough spatial and temporal coverage of annotated genomes to make useful inferences about population dynamics?
Laura Piddock, Canada Research Chairs program, Michael Smith Foundation for
Health Research Scholar program. @jennifergardy
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