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      Pathogen Genomics in Public Health

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          Abstract

          Rapid advances in DNA sequencing technology ("next-generation sequencing") have inspired optimism about the potential of human genomics for "precision medicine." Meanwhile, pathogen genomics is already delivering "precision public health" through more effective investigations of outbreaks of foodborne illnesses, better-targeted tuberculosis control, and more timely and granular influenza surveillance to inform the selection of vaccine strains. In this article, we describe how public health agencies have been adopting pathogen genomics to improve their effectiveness in almost all domains of infectious disease. This momentum is likely to continue, given the ongoing development in sequencing and sequencing-related technologies.

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          Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing.

          Evan S. Snitkin, Adrian M. Zelazny, Pamela Thomas … (2012)
          The Gram-negative bacteria Klebsiella pneumoniae is a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of strains resistant to carbapenems has left few treatment options, making infection containment critical. In 2011, the U.S. National Institutes of Health Clinical Center experienced an outbreak of carbapenem-resistant K. pneumoniae that affected 18 patients, 11 of whom died. Whole-genome sequencing was performed on K. pneumoniae isolates to gain insight into why the outbreak progressed despite early implementation of infection control procedures. Integrated genomic and epidemiological analysis traced the outbreak to three independent transmissions from a single patient who was discharged 3 weeks before the next case became clinically apparent. Additional genomic comparisons provided evidence for unexpected transmission routes, with subsequent mining of epidemiological data pointing to possible explanations for these transmissions. Our analysis demonstrates that integration of genomic and epidemiological data can yield actionable insights and facilitate the control of nosocomial transmission.
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            DNA Sequencing Predicts 1st-Line Tuberculosis Drug Susceptibility Profiles

            Caroline Allix-Beguec, Irena Arandjelovic, Lijun Bi … (2018)
            Background The World Health Organization recommends universal drug susceptibility testing for Mycobacterium tuberculosis complex to guide treatment decisions and improve outcomes. We assessed whether DNA sequencing can accurately predict antibiotic susceptibility profiles for first-line anti-tuberculosis drugs. Methods Whole-genome sequences and associated phenotypes to isoniazid, rifampicin, ethambutol and pyrazinamide were obtained for isolates from 16 countries across six continents. For each isolate, mutations associated with drug-resistance and drug-susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These were predicted to be pan-susceptible if predicted susceptible to isoniazid and to other drugs, or contained mutations of unknown association in genes affecting these other drugs. We simulated how negative predictive value changed with drug-resistance prevalence. Results 10,209 isolates were analysed. The greatest proportion of phenotypes were predicted for rifampicin (9,660/10,130; (95.4%)) and the lowest for ethambutol (8,794/9,794; (89.8%)). Isoniazid, rifampicin, ethambutol and pyrazinamide resistance was correctly predicted with 97.1%, 97.5% 94.6% and 91.3% sensitivity, and susceptibility with 99.0%, 98.8%, 93.6% and 96.8% specificity, respectively. 5,250 (89.5%) drug profiles were correctly predicted for 5,865/7,516 (78.0%) isolates with complete phenotypic profiles. Among these, 3,952/4,037 (97.9%) predictions of pan-susceptibility were correct. The negative predictive value for 97.5% of simulated drug profiles exceeded 95% where the prevalence of drug-resistance was below 47.0%. Conclusions Phenotypic testing for first-line drugs can be phased down in favour of DNA sequencing to guide anti- tuberculosis drug therapy.
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              Next-generation sequencing technologies and their application to the study and control of bacterial infections

              E Trees, J. Besser, H.A. Carleton … (2018)
              Background With the decreasing cost and efficiency of next generation sequencing, the technology is rapidly introduced into clinical and public health laboratory practice. Aims In this review, the historical background and principles of first, second and third generation sequencing are described as are the characteristics of the most commonly used sequencing instruments. Sources Peer reviewed literature, white papers and meeting reports. Content & implications Next generation sequencing is a technology that potentially could replace many traditional microbiological workflows, providing clinicians and public health specialists with more actionable information than hitherto achievable. Examples of the clinical and public health uses of the technology are provided. The challenge of comparability of different sequencing platforms is discussed. Finally, the future directions of the technology integrating it with laboratory management and public health surveillance systems, and moving it towards performing sequencing directly from the clinical specimen (metagenomics) could lead to yet another fundamental transformation of clinical diagnostics and public health surveillance.
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                Author and article information

                Journal
                Title: New England Journal of Medicine
                Abbreviated Title: N Engl J Med
                Publisher: Massachusetts Medical Society
                ISSN (Print): 0028-4793
                ISSN (Electronic): 1533-4406
                Publication date Created: December 26 2019
                Publication date (Print): December 26 2019
                Volume: 381
                Issue: 26
                Pages: 2569-2580
                Affiliations
                [1 ]From the National Center for Emerging and Zoonotic Infectious Diseases (G.L.A., D.R.M., H.A.C.), the National Center for Immunization and Respiratory Diseases (E.B.N.), the Center for Global Health (R.S.B.), and the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (J.E.P.), Centers for Disease Control and Prevention, and CFOL International (M.G.) — all in Atlanta; and the Wadsworth Center, New York State Department of Health, Albany (J.T.).
                Article
                DOI: 10.1056/NEJMsr1813907
                PMC ID: 7008580
                PubMed ID: 31881145
                SO-VID: 70a4371b-f00a-4729-9ee1-561086fffcd0
                Copyright © © 2019
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