. 2018 Feb 15;9(1):694.

doi: 10.1038/s41467-018-03078-2.

A community approach to mortality prediction in sepsis via gene expression analysis

Timothy E Sweeney^{1

2

3}, Thanneer M Perumal⁴, Ricardo Henao^{5

6}, Marshall Nichols⁵, Judith A Howrylak⁷, Augustine M Choi⁸, Jesús F Bermejo-Martin⁹, Raquel Almansa⁹, Eduardo Tamayo⁹, Emma E Davenport^{10

11

12}, Katie L Burnham¹³, Charles J Hinds¹⁴, Julian C Knight¹³, Christopher W Woods^{5

15

16}, Stephen F Kingsmore¹⁷, Geoffrey S Ginsburg⁵, Hector R Wong^{18

19}, Grant P Parnell²⁰, Benjamin Tang^{20

21

22

23}, Lyle L Moldawer²⁴, Frederick E Moore²⁴, Larsson Omberg⁴, Purvesh Khatri^{1

2}, Ephraim L Tsalik^{5

15

16}, Lara M Mangravite⁴, Raymond J Langley²⁵

Affiliations

¹ Stanford Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Division of Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Inflammatix Inc., Burlingame, CA, 94010, USA.
⁴ Sage Bionetworks, Seattle, WA, 98109, USA.
⁵ Center for Applied Genomics and Precision Medicine, Department of Medicine, Duke University, Durham, NC, 27708, USA.
⁶ Department of Electrical and Computer Engineering, Duke University, Durham, NC, 27708, USA.
⁷ Division of Pulmonary and Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA.
⁸ Department of Medicine, Cornell Medical Center, New York, NY, 10065, USA.
⁹ Hospital Clínico Universitario de Valladolid/IECSCYL, Valladolid, 47005, Spain.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Partners Center for Personalized Genetic Medicine, Boston, MA, 02115, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹³ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
¹⁴ William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University, London, EC1M 6BQ, UK.
¹⁵ Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, NC, 27710, USA.
¹⁶ Durham Veteran's Affairs Health Care System, Durham, NC, 27705, USA.
¹⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA.
¹⁸ Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, 45223, USA.
¹⁹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
²⁰ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead, NSW, 2145, Australia.
²¹ Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia, Penrith, NSW, 2751, Australia.
²² Nepean Genomic Research Group, Nepean Clinical School, University of Sydney, Penrith, NSW, 2751, Australia.
²³ Marie Bashir Institute for Infectious Diseases and Biosecurity, Westmead, NSW, 2145, Australia.
²⁴ Department of Surgery, University of Florida College of Medicine, Gainesville, FL, 32610, USA.
²⁵ Department of Pharmacology, University of South Alabama, Mobile, AL, 36688, USA. rlangley@southalabama.edu.

PMID: 29449546
PMCID: PMC5814463
DOI: 10.1038/s41467-018-03078-2

A community approach to mortality prediction in sepsis via gene expression analysis

Timothy E Sweeney et al. Nat Commun. 2018.

. 2018 Feb 15;9(1):694.

doi: 10.1038/s41467-018-03078-2.

Authors

Affiliations

¹ Stanford Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Division of Biomedical Informatics Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Inflammatix Inc., Burlingame, CA, 94010, USA.
⁴ Sage Bionetworks, Seattle, WA, 98109, USA.
⁵ Center for Applied Genomics and Precision Medicine, Department of Medicine, Duke University, Durham, NC, 27708, USA.
⁶ Department of Electrical and Computer Engineering, Duke University, Durham, NC, 27708, USA.
⁷ Division of Pulmonary and Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA.
⁸ Department of Medicine, Cornell Medical Center, New York, NY, 10065, USA.
⁹ Hospital Clínico Universitario de Valladolid/IECSCYL, Valladolid, 47005, Spain.
¹⁰ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
¹¹ Partners Center for Personalized Genetic Medicine, Boston, MA, 02115, USA.
¹² Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
¹³ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
¹⁴ William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University, London, EC1M 6BQ, UK.
¹⁵ Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, NC, 27710, USA.
¹⁶ Durham Veteran's Affairs Health Care System, Durham, NC, 27705, USA.
¹⁷ Rady Children's Institute for Genomic Medicine, San Diego, CA, 92123, USA.
¹⁸ Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center and Cincinnati Children's Research Foundation, Cincinnati, OH, 45223, USA.
¹⁹ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
²⁰ Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead, NSW, 2145, Australia.
²¹ Department of Intensive Care Medicine, Nepean Hospital, Sydney, Australia, Penrith, NSW, 2751, Australia.
²² Nepean Genomic Research Group, Nepean Clinical School, University of Sydney, Penrith, NSW, 2751, Australia.
²³ Marie Bashir Institute for Infectious Diseases and Biosecurity, Westmead, NSW, 2145, Australia.
²⁴ Department of Surgery, University of Florida College of Medicine, Gainesville, FL, 32610, USA.
²⁵ Department of Pharmacology, University of South Alabama, Mobile, AL, 36688, USA. rlangley@southalabama.edu.

PMID: 29449546
PMCID: PMC5814463
DOI: 10.1038/s41467-018-03078-2

Abstract

Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765-0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis.

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Conflict of interest statement

The ‘Duke’ 18-gene score is the subject of a provisional patent filed by Duke University. The ‘Stanford’ 12-gene score is the subject of a provisional patent filed by Stanford University. T.E.S. and P.K. are co-founders of Inflammatix, Inc., which has a commercial interest in the ‘Stanford’ 12-gene score. The remaining authors declare no competing financial interests.

Figures

**Fig. 1**
Overview of analysis: schema of our community-modeling-based approach to multi-cohort analysis. Three phases are shown, as described in the Methods section: (i) discovery, (ii) validation, and (iii) secondary validation (HAI cohorts)

**Fig. 2**
Model performance of the four genomic mortality predictors as measured by (a) AUROC and (b) AUPRC. The three panels (top, middle, bottom) show boxplots of the performance across all Discovery, Validation, and HAI cohorts

See this image and copyright information in PMC

References

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A community approach to mortality prediction in sepsis via gene expression analysis

Affiliations

A community approach to mortality prediction in sepsis via gene expression analysis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

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Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical