Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis

M. Man; S. L. Close; A. D. Shaw; G. R. Bernard; I. S. Douglas; R. J. Kaner; D. Payen; J. L. Vincent; S. Fossceco; J. M. Janes; A. G. Leishman; L. O'Brien; M. D. Williams; J. G.N. Garcia

doi:10.1038/tpj.2012.1

Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis

M. Man, S. L. Close, A. D. Shaw, G. R. Bernard, I. S. Douglas, R. J. Kaner, D. Payen, J. L. Vincent, S. Fossceco, J. M. Janes, A. G. Leishman, L. O'Brien, M. D. Williams, J. G.N. Garcia

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38 Scopus citations

Abstract

Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.

Original language	English (US)
Pages (from-to)	218-226
Number of pages	9
Journal	Pharmacogenomics Journal
Volume	13
Issue number	3
DOIs	https://doi.org/10.1038/tpj.2012.1
State	Published - Jun 2013
Externally published	Yes

Keywords

Drotrecogin alfa (activated)
epistasis
genetic markers
genome-wide association study
polymorphism
severe sepsis

ASJC Scopus subject areas

Molecular Medicine
Genetics
Pharmacology

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10.1038/tpj.2012.1

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Man, M., Close, S. L., Shaw, A. D., Bernard, G. R., Douglas, I. S., Kaner, R. J., Payen, D., Vincent, J. L., Fossceco, S., Janes, J. M., Leishman, A. G., O'Brien, L., Williams, M. D., & Garcia, J. G. N. (2013). Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis. Pharmacogenomics Journal, 13(3), 218-226. https://doi.org/10.1038/tpj.2012.1

Man, M, Close, SL, Shaw, AD, Bernard, GR, Douglas, IS, Kaner, RJ, Payen, D, Vincent, JL, Fossceco, S, Janes, JM, Leishman, AG, O'Brien, L, Williams, MD & Garcia, JGN 2013, 'Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis', Pharmacogenomics Journal, vol. 13, no. 3, pp. 218-226. https://doi.org/10.1038/tpj.2012.1

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title = "Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis",

abstract = "Management of severe sepsis, an acute illness with high morbidity and mortality, suffers from the lack of effective biomarkers and largely empirical predictions of disease progression and therapeutic responses. We conducted a genome-wide association study using a large randomized clinical trial cohort to discover genetic biomarkers of response to therapy and prognosis utilizing novel approaches, including combination markers, to overcome limitations of single-marker analyses. Sepsis prognostic models were dominated by clinical variables with genetic markers less informative. In contrast, evidence for gene-gene interactions were identified for sepsis treatment responses with genetic biomarkers dominating models for predicting therapeutic responses, yielding candidates for replication in other cohorts.",

keywords = "Drotrecogin alfa (activated), epistasis, genetic markers, genome-wide association study, polymorphism, severe sepsis",

author = "M. Man and Close, {S. L.} and Shaw, {A. D.} and Bernard, {G. R.} and Douglas, {I. S.} and Kaner, {R. J.} and D. Payen and Vincent, {J. L.} and S. Fossceco and Janes, {J. M.} and Leishman, {A. G.} and L. O'Brien and Williams, {M. D.} and Garcia, {J. G.N.}",

note = "Funding Information: Financial support for this study was provided by Eli Lilly and Company. We thank Michael Bell and Cindy Lee (both Eli Lilly and Company), Duytrac Nguyen (Inventiv Clinical), and Jared Kohler and Angela Prokop (both BioStat Solutions) for assistance in statistical analysis. We also thank Julie Sherman (Eli Lilly and Company) for technical assistance with the illustrations.",

year = "2013",

month = jun,

doi = "10.1038/tpj.2012.1",

language = "English (US)",

volume = "13",

pages = "218--226",

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AU - Man, M.

AU - Close, S. L.

AU - Shaw, A. D.

AU - Bernard, G. R.

AU - Douglas, I. S.

AU - Kaner, R. J.

AU - Payen, D.

AU - Vincent, J. L.

AU - Fossceco, S.

AU - Janes, J. M.

AU - Leishman, A. G.

AU - O'Brien, L.

AU - Williams, M. D.

AU - Garcia, J. G.N.

N1 - Funding Information: Financial support for this study was provided by Eli Lilly and Company. We thank Michael Bell and Cindy Lee (both Eli Lilly and Company), Duytrac Nguyen (Inventiv Clinical), and Jared Kohler and Angela Prokop (both BioStat Solutions) for assistance in statistical analysis. We also thank Julie Sherman (Eli Lilly and Company) for technical assistance with the illustrations.

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Beyond single-marker analyses: Mining whole genome scans for insights into treatment responses in severe sepsis

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Keywords

ASJC Scopus subject areas

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