Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger

Prashant Mahajan, Nathan Kuppermann, Asuncion Mejias, Nicolas Suarez, Damien J. Chaussabel, T. Charles Casper, Bennett Smith, Elizabeth R. Alpern, Jennifer Anders, Shireen M. Atabaki, Jonathan E. Bennett, Stephen Blumberg, Bema Bonsu, Dominic Borgialli, Anne Brayer, Lorin Browne, Daniel M. Cohen, Ellen F. Crain, Andrea T. Cruz, Peter S. Dayan & 19 others Rajender Gattu, Richard Greenberg, John D. Hoyle, David M. Jaffe, Deborah A. Levine, Kathleen Lillis, James G. Linakis, Jared Muenzer, Lise E. Nigrovic, Elizabeth C. Powell, Alexander J. Rogers, Genie Roosevelt, Richard M. Ruddy, Mary Saunders, Michael G. Tunik, Leah Tzimenatos, Melissa Vitale, J. Michael Dean, Octavio Ramilo

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

IMPORTANCE Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ('RNA biosignatures') in response to infections may provide an alternative diagnostic approach. OBJECTIVE To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature <38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS Of 1883 febrile infants (median age, 37 days; 55.7%boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87%(95%CI, 73%-95%) sensitivity and 89%(95%CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94%(95%CI, 70%-100%) sensitivity and 95%(95%CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95%CI, 0.30-0.43). CONCLUSIONS AND RELEVANCE In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with and without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

Original languageEnglish
Pages (from-to)846-857
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume316
Issue number8
DOIs
Publication statusPublished - 23 Aug 2016
Externally publishedYes

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Bacterial Infections
Fever
RNA
Bacteremia
Observation
Infection
Computational Biology
Genes
Observational Studies
Hospital Emergency Service
Prospective Studies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. / Mahajan, Prashant; Kuppermann, Nathan; Mejias, Asuncion; Suarez, Nicolas; Chaussabel, Damien J.; Casper, T. Charles; Smith, Bennett; Alpern, Elizabeth R.; Anders, Jennifer; Atabaki, Shireen M.; Bennett, Jonathan E.; Blumberg, Stephen; Bonsu, Bema; Borgialli, Dominic; Brayer, Anne; Browne, Lorin; Cohen, Daniel M.; Crain, Ellen F.; Cruz, Andrea T.; Dayan, Peter S.; Gattu, Rajender; Greenberg, Richard; Hoyle, John D.; Jaffe, David M.; Levine, Deborah A.; Lillis, Kathleen; Linakis, James G.; Muenzer, Jared; Nigrovic, Lise E.; Powell, Elizabeth C.; Rogers, Alexander J.; Roosevelt, Genie; Ruddy, Richard M.; Saunders, Mary; Tunik, Michael G.; Tzimenatos, Leah; Vitale, Melissa; Dean, J. Michael; Ramilo, Octavio.

In: JAMA - Journal of the American Medical Association, Vol. 316, No. 8, 23.08.2016, p. 846-857.

Research output: Contribution to journalArticle

Mahajan, P, Kuppermann, N, Mejias, A, Suarez, N, Chaussabel, DJ, Casper, TC, Smith, B, Alpern, ER, Anders, J, Atabaki, SM, Bennett, JE, Blumberg, S, Bonsu, B, Borgialli, D, Brayer, A, Browne, L, Cohen, DM, Crain, EF, Cruz, AT, Dayan, PS, Gattu, R, Greenberg, R, Hoyle, JD, Jaffe, DM, Levine, DA, Lillis, K, Linakis, JG, Muenzer, J, Nigrovic, LE, Powell, EC, Rogers, AJ, Roosevelt, G, Ruddy, RM, Saunders, M, Tunik, MG, Tzimenatos, L, Vitale, M, Dean, JM & Ramilo, O 2016, 'Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger', JAMA - Journal of the American Medical Association, vol. 316, no. 8, pp. 846-857. https://doi.org/10.1001/jama.2016.9207
Mahajan, Prashant ; Kuppermann, Nathan ; Mejias, Asuncion ; Suarez, Nicolas ; Chaussabel, Damien J. ; Casper, T. Charles ; Smith, Bennett ; Alpern, Elizabeth R. ; Anders, Jennifer ; Atabaki, Shireen M. ; Bennett, Jonathan E. ; Blumberg, Stephen ; Bonsu, Bema ; Borgialli, Dominic ; Brayer, Anne ; Browne, Lorin ; Cohen, Daniel M. ; Crain, Ellen F. ; Cruz, Andrea T. ; Dayan, Peter S. ; Gattu, Rajender ; Greenberg, Richard ; Hoyle, John D. ; Jaffe, David M. ; Levine, Deborah A. ; Lillis, Kathleen ; Linakis, James G. ; Muenzer, Jared ; Nigrovic, Lise E. ; Powell, Elizabeth C. ; Rogers, Alexander J. ; Roosevelt, Genie ; Ruddy, Richard M. ; Saunders, Mary ; Tunik, Michael G. ; Tzimenatos, Leah ; Vitale, Melissa ; Dean, J. Michael ; Ramilo, Octavio. / Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger. In: JAMA - Journal of the American Medical Association. 2016 ; Vol. 316, No. 8. pp. 846-857.
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abstract = "IMPORTANCE Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ('RNA biosignatures') in response to infections may provide an alternative diagnostic approach. OBJECTIVE To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature <38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS Of 1883 febrile infants (median age, 37 days; 55.7{\%}boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87{\%}(95{\%}CI, 73{\%}-95{\%}) sensitivity and 89{\%}(95{\%}CI, 81{\%}-93{\%}) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94{\%}(95{\%}CI, 70{\%}-100{\%}) sensitivity and 95{\%}(95{\%}CI, 88{\%}-98{\%}) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95{\%}CI, 0.30-0.43). CONCLUSIONS AND RELEVANCE In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with and without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.",
author = "Prashant Mahajan and Nathan Kuppermann and Asuncion Mejias and Nicolas Suarez and Chaussabel, {Damien J.} and Casper, {T. Charles} and Bennett Smith and Alpern, {Elizabeth R.} and Jennifer Anders and Atabaki, {Shireen M.} and Bennett, {Jonathan E.} and Stephen Blumberg and Bema Bonsu and Dominic Borgialli and Anne Brayer and Lorin Browne and Cohen, {Daniel M.} and Crain, {Ellen F.} and Cruz, {Andrea T.} and Dayan, {Peter S.} and Rajender Gattu and Richard Greenberg and Hoyle, {John D.} and Jaffe, {David M.} and Levine, {Deborah A.} and Kathleen Lillis and Linakis, {James G.} and Jared Muenzer and Nigrovic, {Lise E.} and Powell, {Elizabeth C.} and Rogers, {Alexander J.} and Genie Roosevelt and Ruddy, {Richard M.} and Mary Saunders and Tunik, {Michael G.} and Leah Tzimenatos and Melissa Vitale and Dean, {J. Michael} and Octavio Ramilo",
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TY - JOUR

T1 - Association of RNA biosignatures with bacterial infections in febrile infants aged 60 days or younger

AU - Mahajan, Prashant

AU - Kuppermann, Nathan

AU - Mejias, Asuncion

AU - Suarez, Nicolas

AU - Chaussabel, Damien J.

AU - Casper, T. Charles

AU - Smith, Bennett

AU - Alpern, Elizabeth R.

AU - Anders, Jennifer

AU - Atabaki, Shireen M.

AU - Bennett, Jonathan E.

AU - Blumberg, Stephen

AU - Bonsu, Bema

AU - Borgialli, Dominic

AU - Brayer, Anne

AU - Browne, Lorin

AU - Cohen, Daniel M.

AU - Crain, Ellen F.

AU - Cruz, Andrea T.

AU - Dayan, Peter S.

AU - Gattu, Rajender

AU - Greenberg, Richard

AU - Hoyle, John D.

AU - Jaffe, David M.

AU - Levine, Deborah A.

AU - Lillis, Kathleen

AU - Linakis, James G.

AU - Muenzer, Jared

AU - Nigrovic, Lise E.

AU - Powell, Elizabeth C.

AU - Rogers, Alexander J.

AU - Roosevelt, Genie

AU - Ruddy, Richard M.

AU - Saunders, Mary

AU - Tunik, Michael G.

AU - Tzimenatos, Leah

AU - Vitale, Melissa

AU - Dean, J. Michael

AU - Ramilo, Octavio

PY - 2016/8/23

Y1 - 2016/8/23

N2 - IMPORTANCE Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ('RNA biosignatures') in response to infections may provide an alternative diagnostic approach. OBJECTIVE To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature <38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS Of 1883 febrile infants (median age, 37 days; 55.7%boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87%(95%CI, 73%-95%) sensitivity and 89%(95%CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94%(95%CI, 70%-100%) sensitivity and 95%(95%CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95%CI, 0.30-0.43). CONCLUSIONS AND RELEVANCE In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with and without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

AB - IMPORTANCE Young febrile infants are at substantial risk of serious bacterial infections; however, the current culture-based diagnosis has limitations. Analysis of host expression patterns ('RNA biosignatures') in response to infections may provide an alternative diagnostic approach. OBJECTIVE To assess whether RNA biosignatures can distinguish febrile infants aged 60 days or younger with and without serious bacterial infections. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study involving a convenience sample of febrile infants 60 days or younger evaluated for fever (temperature <38° C) in 22 emergency departments from December 2008 to December 2010 who underwent laboratory evaluations including blood cultures. A random sample of infants with and without bacterial infections was selected for RNA biosignature analysis. Afebrile healthy infants served as controls. Blood samples were collected for cultures and RNA biosignatures. Bioinformatics tools were applied to define RNA biosignatures to classify febrile infants by infection type. EXPOSURE RNA biosignatures compared with cultures for discriminating febrile infants with and without bacterial infections and infants with bacteremia from those without bacterial infections. MAIN OUTCOMES AND MEASURES Bacterial infection confirmed by culture. Performance of RNA biosignatures was compared with routine laboratory screening tests and Yale Observation Scale (YOS) scores. RESULTS Of 1883 febrile infants (median age, 37 days; 55.7%boys), RNA biosignatures were measured in 279 randomly selected infants (89 with bacterial infections-including 32 with bacteremia and 190 without bacterial infections), and 19 afebrile healthy infants. Sixty-six classifier genes were identified that distinguished infants with and without bacterial infections in the test set with 87%(95%CI, 73%-95%) sensitivity and 89%(95%CI, 81%-93%) specificity. Ten classifier genes distinguished infants with bacteremia from those without bacterial infections in the test set with 94%(95%CI, 70%-100%) sensitivity and 95%(95%CI, 88%-98%) specificity. The incremental C statistic for the RNA biosignatures over the YOS score was 0.37 (95%CI, 0.30-0.43). CONCLUSIONS AND RELEVANCE In this preliminary study, RNA biosignatures were defined to distinguish febrile infants aged 60 days or younger with and without bacterial infections. Further research with larger populations is needed to refine and validate the estimates of test accuracy and to assess the clinical utility of RNA biosignatures in practice.

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