genomics in public health
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genomics in public healthTracking & treating disease with DNA sequencing
Dr. Jennifer Gardy, BC Centre for Disease Control @jennifergardy jennifer.gardy@bccdc.ca
HelLO!
Senior Scientist (Genomics), BCCDC Asst. Professor, UBC SPPH
Canada Research Chair in Public Health Genomics
agenda of funWhere does microbiology fit in public health? What are we doing now? Diagnostics & outbreaks The genomics revolution Current genomics approaches in public health microbiology Future directions
Goal: show you a very cool domain where interesting genomics is maybe going to prevent
us all from dying of something awful
public health (noun, \ˈpə-blik ˈhelth\): the organized efforts of society to keep people healthy and prevent injury, illness and premature death, combining programs, services and policies that protect and promote people’s health.
patient sample for diagnosis what does this patient have? how should I treat them?
study sample for surveillance what is circulating in our population? what does this mean for PH?
environmental sample what is circulating in our water, food? what does this mean for PH?
communicable disease surveillance
• multiple data streams: lab positives, other reports, physician billing codes, alert healthcare workers
• what is out there? • is there more than usual? • are blips due to an outbreak?
Restriction digest (RFLP) Multilocus sequence typing (MLST) Multilocus variable number
tandem repeat analysis (MLVA/VNTR)
RFLP MLST/MLVA
Enzymes cleave chromosome into large fragments
PCR primers amplify specific regions of the chromosome
RFLP MLST/MLVA
The whole chromosome, broken into a few pieces
A few short fragments of the chromosome
RFLP MLST/MLVA
The whole chromosome, broken into a few pieces
Run on a gel
A few short fragments of the chromosome
Compare against database
Basic Principles of Field Epidemiology • Identify cases and controls • Structured or semi-structured interview • Data collated into a line list • Combined with clinical data to infer likely exposures and
transmissions
BUT WAIT. WE HAVE A PROBLEM. • Genotyping methods only tell you a cluster of cases exists, not the order/
direction of transmission • Size/membership of the cluster varies with the typing method(s) used • Epidemiological investigation is required to derive the links between cases,
and may not be available or of sufficient qualitY
a summary of our roadblocks
diagnostics: time-consuming, require suspicion, variable performance, still many “unknown” samples phenotypic dst: sloooooooooooooooooow surveillance: low-resolution typing techniques, heavily reliant on field epidemiological data the whole process: multiple parallel steps, reporting at various stages throughout the process
are these roadblocks any more?
diagnostics: time-consuming, require suspicion, variable performance, still many “unknown” samples phenotypic dst: sloooooooooooooooooow surveillance: low-resolution typing techniques, heavily reliant on field epidemiological data the whole process: multiple parallel steps, reporting at various stages throughout the process
agenda of funWhere does microbiology fit in public health? What are we doing now? The genomics revolution Current genomics approaches in public health microbiology Future directions
“Joshua Osborn, 14, lay in a coma at American Family Children’s Hospital in Madison, Wis. For
weeks his brain had been swelling with fluid, and a battery of tests had failed to reveal the cause.”
–Carl Zimmer, New York Times, June 2014
“Joshua’s cerebrospinal fluid contained DNA from a potentially lethal type of bacteria called Leptospira…readily treated with penicillin…
That afternoon, Joshua started getting large doses of penicillin. The swelling in his brain almost immediately started subsiding, and two
weeks after the first test results, Joshua was walking.”
genomics for diagnostics
• FROM CULTURE OR DIRECT FROM SPECIMEN
• SEQUENCE SAMPLE, REMOVE HUMAN READS, COMPARE TO DATABASE OF KNOWN SEQUENCES (BUT WHO’S WHO?)
• FASTER THAN NAAT IN SOME CASES, BUT NOT ALL
Clinical metagenomics toolbox: • Nanopore for near-patient sequencing • Illumina for slightly longer turnaround • Metagenomics pipeline for binning reads (e.g. SURPI) • ID physician to make the call on commensal vs pathogen
ACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACG
ATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACG
TACGATCGACGTACGATCGACGTACGATCGACGTACGATCGCGCCGGACGTACGATCGACGTACGATCGACGT
ACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCG
ACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACG
ATCGACGTACGATCGACGTACGATCG
ACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACG
ATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACG
TACGATCGACGTACGATCGACGTACGATCGACGTACGATCGCGCCGGACGTACGATCGACGTACGATCGACGT
ACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCG
ACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACGATCGACGTACG
ATCGACGTACGATCGACGTACGATCG
Personalized therapy toolbox: • Illumina sequencing at reference lab • Rapid resistance prediction from genomic data (e.g. Mykrobe) • Growing catalogue of resistance-associated mutations
ge·no·mic ep·i·de·mi·ol·o·gy (jēˈnōmik ˌepiˌdēmēˈäləjē/) n. reading whole genome sequences from outbreak isolates to track person-to-person spread of an infectious disease.
detour: reconstructing a transmission network in the
light of within-host diversity
With xavier didelot & caroline colijn
¯\_( )_/¯direct observation of within-host diversity may not be possible
due to the nature of infection and specimen collection
TIME IN THE SHELTER WAS ASSOCIATED WITH INCREASED RISK OF INFECTION (OR 1.26), ESPECIALLY STAYS OF 5+ NIGHTS (OR 4.97)
by 2014, the outbreak had grown to 52 cases and 2310 screened clients.
COULD THE OUTBREAK BE DECLARED OVER?
2008 2009 2010 2011 2012 2013
7 7
11 12
86
1
MEMO
Bus: (250) 868-7818 Fax: (250) 868-7826 Kelowna Health Centre Email: sue.pollock@interiorhealth.ca 1340 Ellis Street www.interiorhealth.ca Kelowna, BC V1Y 9N1
Quality y Integrity y Respect y Trust
In 2008, an outbreak of Mycobacterium Tuberculosis (TB) was declared after a higher-than-expected number of TB cases were identified in the Central Okanagan. Between 2008 and 2014, 52 outbreak-related active TB cases were identified. Most cases were homeless and/or street-involved persons in Kelowna with a small linked cluster in Penticton, and several cases in Salmon Arm. Interior Health’s TB Outbreak Management Team, in partnership with community organizations and the BC Centre for Disease Control have used numerous strategies to identify and treat new cases and to minimize the public health risk. Epidemiological and genomics (genetic fingerprinting) data demonstrate that the peak of the outbreak occurred in late 2010/early 2011. There is currently no evidence of ongoing transmission and incidence of new TB cases has returned to baseline (pre-outbreak) levels.
The Central Okanagan TB outbreak is declared over as of January 29, 2015. We expect to see sporadic new TB diagnoses connected to the outbreak in the coming years; early detection of these cases will be critical to preventing another outbreak. The CD Unit will disseminate further information about next steps as the outbreak response is de-escalated. Outbreaks of TB among homeless persons are strongly related to social determinants of health such as employment, income, safe housing, and access to health care. Preventing and controlling future outbreaks requires continued attention to these inequities through comprehensive policies and programs that aim to reduce health disparities in our community. On behalf of the Office of the Medical Health Officers, we thank each of you for your hard work and collaboration in controlling this outbreak and for your continued dedication to TB prevention and control. If you have any questions, please contact the Communicable Disease Unit at 1-866-778-7736 or by email CDUnit@interiorhealth.ca.
To: CIHS Promotion & Prevention; Infection Control, Workplace Health & Safety, KGH Administrators, PRH Administrators, Senior Executive Team, CD Unit
From: Dr. Sue Pollock, Medical Health Officer & Medical Director, Communicable Disease
Date: February 4, 2015
RE: Central Okanagan TB Outbreak Declared Over
1. understand epidemic dynamics
Group A Streptococcus PMID: 20142485
1. Sequence & assemble genomes of pathogens sampled from an epidemic (an outbreak spanning a large region)
2. Build a phylogeny to identify clades - “subclones” 3. Plot the prevalence of subclones across space and/or time
to understand why/how the epidemic is happening
2. discover a brand-new pathogen
Bas-Congo virus PMID: 23028323
1. Do metagenomics on a sample from a patient with an unknown disease
2. BLAST reads against a database of all known organisms
3. Look in the set of reads that didn’t match to any known organisms
4. Try some lab tricks to sequence the whole virus
3. describe a novel pathogen
German outbreak E. coli O104:H4 PMID: 21793740
1. Sequence & assemble genome(s) of novel pathogen 2. Build a phylogeny to see how it relates to other members of
its genus 3. Do comparative genomics to identify genes/elements
present or absent in new pathogen relative to other species
PMC4556809
PMC4587932
4. understand the drivers and
evolution of within-host and
population-level evolution
of resistance.
5. date the time of a viral infection
HIV PMID: 218322936
1. Sequence all the viruses found in a patient (the viral “quasispecies”)
2. Build a phylogenetic tree where branch lengths correspond to calendar time
3. Identify the time of the TMRCA - this is the infection time
6. therapeutic monitoring of DRUG resistance
HIV PMID: 20628644
1. Sequence all the viruses found in a patient (“quasispecies”) at multiple times throughout their ART treatment
2. Scan the sequences for known mutations that confer drug resistance - if you see them, change the treatment plan
DIAGN
OSIS
1. Sensitivity in sequencing directly from a clinical sample
2. Clinical metagenomics - who’s the pathogen, who’s a commensal, who’s a contaminant?
3. Building lab capacity
RESIS
TANC
E PRE
DICTIO
N1. 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?
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?
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