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Review
. 2012;8(8):e1002824.
doi: 10.1371/journal.ppat.1002824. Epub 2012 Aug 2.

Routine use of microbial whole genome sequencing in diagnostic and public health microbiology

Claudio U Köser  1 , Matthew J Ellington, Edward J P Cartwright, Stephen H Gillespie, Nicholas M Brown, Mark Farrington, Matthew T G Holden, Gordon Dougan, Stephen D Bentley, Julian Parkhill, Sharon J Peacock
Affiliations
Review

Routine use of microbial whole genome sequencing in diagnostic and public health microbiology

Claudio U Köser et al. PLoS Pathog. 2012.
No abstract available

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Conflict of interest statement

I have read the journal's policy and have the following conflicts: CUK, MJE, EJPC, NMB, MTGH, GD, SDB, JP, and SJP have collaborated with Illumina Ltd. on a number of scientific projects. JP has received funding for travel and accommodation from Pacific Biosciences Inc. and Illumina Inc. NMB is a consultant for Astellas Pharma Ltd. SHG has received payments from Bayer Schering Health Care for lectures. SJP is a consultant for Pfizer Inc. This does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.

Figures

Figure 1
Figure 1. Potential impact of whole genome sequencing in diagnostic and public health microbiology.
Clinical samples processed by diagnostic microbiology laboratories commonly pass through up to four stages, characterised by a stepwise decrease in the number of samples analysed at each successive stage and an inverse association with turn-around time (TAT), labour, and costs (shown in dark blue). Detection, identification, and susceptibility testing in virology are achieved using serological or molecular methods, whereas bacteriology generally relies on phenotypic methods. Epidemiological typing is only done for a handful of organisms using molecular and sometimes phenotypic methods. The most compelling immediate applications for WGS are molecular epidemiology for the purposes of surveillance and outbreak investigation (e.g. for MRSA) and drug susceptibility testing for organisms that are either slow growers or difficult to culture (e.g. MTBC and HIV). This is likely to lead to more samples being typed than is currently the case (depicted in purple), all while drastically reducing turnaround times, provided that WGS is performed in a regional or local laboratory rather than a reference centre. Assuming that this information enables cost-effective clinical interventions, the number of pathogens sequenced is likely to increase over time. Approaches to detection and identification of pathogens and the majority of susceptibility testing are likely to remain largely unchanged in the near future.
Figure 2
Figure 2. Overview of pathogen WGS data interpretation and use.
After an enrichment step for pathogen DNA via culture or direct molecular enrichment/amplification (e.g. by RT-PCR for HIV) from the clinical sample, WGS could be performed in regional sequencing hubs. Fully automated analysis software would extract information of immediate clinical importance (i.e. an epidemiological analysis, susceptibility testing, and/or the precise identity of the pathogen). The results would be presented such that no knowledge of genomics would be required. Only in cases of new and emerging types of concern, where the genotype-phenotype relationship was unclear, or for quality control (QC) purposes would samples be sent for analysis by reference laboratories. Reference laboratories could routinely make anonymised sequence data available in the first part of an international online encyclopaedia to spur basic as well as translational research via a user-friendly interface to analyse whole genomes. Moreover, they could perform routine in silico surveillance of all genomes in their respective countries to relate treatment outcomes to particular genotypes or mutations. Clinically relevant surveillance results such as the discovery of novel pathogens or new markers for drug-resistance could be shared with appropriate international bodies and ultimately deposited in the encyclopaedia . A forum could provide an opportunity for the scientific community to contribute and discuss findings with clinical implications. Novel markers would require review by an expert panel and, if approved, be incorporated into the read-only diagnostic database containing a catalogue of known resistance markers, which would then be used clinically by the automated WGS interpretation software.
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