• Discovery of Stratification and Diagnostic Biomarkers

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    PERSEVERE is a multi-biomarker-based risk model to predict outcome and illness severity for individual children with septic shock. The candidate stratification biomarkers have been selected in a systematic and unbiased manner using our gene expression database. The model was derived and validated in collaboration with Christopher Lindsell, PhD, The serum candidate biomarkers are measured using a multiplex platform developed in collaboration with the Millipore Corp. PERSEVERE was funded by an American Recovery and Reinvestment Act Challenge Grant sponsored by the National Heart, Lung and Blood Institute.

    We have also received an Innovation Fund Award from the Cincinnati Children's Center for Technology Commercialization.

    List of candidate stratification biomarkers for PERSEVERE.

    We have also adapted PERSEVERE for use in adults with severe sepsis and septic shock. The adult version of PERSEVERE is called ASSIST (Adult Septic Shock Information and Stratification Technology). ASSIST was developed in collaboration with investigators from the Centre for Heart Lung Innovation, University of British Columbia and St. Paul’s Hospital, the FINNSepsis Study Group, and the University of Pennsylvania

    Decision tree for PERSEVERE.
    Decision tree for PERSEVERE.
    Click image to view full screen.

    References
    1. Wong, H.R., K.R. Walley, V. Pettilä, N.J. Meyer, J.A. Russell, S. Karlsson, M.G.S. Shashaty, and C.J. Lindsell. Comparing the prognostic performance of ASSIST to interleukin-6 and procalcitonin in patients with severe sepsis and septic shock. Biomarkers. 2015 (in press).
    2. Alder, M.N., C.J. Lindsell, and H.R. Wong. The pediatric sepsis biomarker risk model:  Potential implications for sepsis therapy and biology. Expert Rev Anti Infect Ther. 12:809-815, 2014.
    3. Wong, H.R., C.J. Lindsell, V. Pettilä, N.J. Meyer, S.A. Thair, S. Karlsson, J.A. Russell, C.D. Fjell, J.H. Boyd, E. Ruokonen, M.G.S. Shashaty, J.D. Christie, K.W. Hart. P. Lahni, and K.R. Walley. A multi-biomarker-based outcome risk stratification model for adult septic shock. Crit Care Med. 42:781-789, 2014.
    4. Wong, H.R., S.L. Weiss, J.S. Giuliano, Jr., M.S. Wainwright, N.Z. Cvijanovich, N.J. Thomas, G.L. Allen, N. Anas, M.T. Bigham, M. Hall, R.J. Freishtat, A. Sen, K. Meyer, P.A. Checchia, T.P. Shanley, J. Nowak, M. Quasney, A. Chopra, J.C. Fitzgerald, R. Gedeit,  S. Banschbach, E. Beckman, K. Harmon, P. Lahni, and C.J. Lindsell. The temporal version of the pediatric sepsis biomarker risk model. PLoS One. 9:e92121, 2014.
    5. Wong, H.R., S.L. Weiss, J.S. Giuliano, Jr., M.S. Wainwright, N.Z. Cvijanovich, N.J. Thomas, G.L. Allen, N. Anas, M.T. Bigham, M. Hall, R.J. Freishtat, A. Sen, K. Meyer, P.A. Checchia, T.P. Shanley, J. Nowak, M. Quasney, A. Chopra, J.C. Fitzgerald, R. Gedeit,  S. Banschbach, E. Beckman, P. Lahni, K. Hart, and C.J. Lindsell. Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model. PLoS One. (9):e86242, 2014.
    6. Wong, H.R., S. Salisbury, Q. Xiao, N.Z. Cvijanovich, M. Hall, G.L. Allen, N.J. Thomas, R.J. Freishtat, N. Anas, K. Meyer, P.A. Checchia, R. Lin, T.P. Shanley, M.T. Bigham, A. Sen, J. Nowak, M. Quasney, J.W. Hendricksen, A. Chopra, S. Banschbach, E. Beckman, K. Harmon, P. Lahni, and C.J. Lindsell. The pediatric sepsis biomarker risk model. Crit Care. 16:R174, 2012.
    7. Kaplan, J.M. and Wong, H.R. Biomarker discovery and development in pediatric critical care medicine. Ped Crit Care Med. 12:165-173, 2011.
    8. Standage, S.W. and Wong, H.R. Biomarkers for pediatric sepsis and septic shock. Expert Rev Anti Infect Ther. 1:71-79, 2011.

    In collaboration with the Center for Acute Care Nephrology at Cincinnati Children’s, we have recently derived a list of 21 candidate genes to predict persistent, severe, septic shock-associated kidney injury within 24 hours of admission to the pediatric intensive care unit. These 21 genes are being further explored to identify serum-based biomarkers for septic shock associated kidney injury via a recently awarded grant from the National Institutes of Health.

    Twenty-one candidate stratification genes for predicting septic shock-associated kidney injury.

    References
    1. Basu, R.K., Standage, S.W., Cvijanovich, N.Z., Allen, G.L., Thomas, N.J., Freishtat, R.J., Anas, N., Meyer, K., Checchia, P.A., Lin, R., Shanley, T.P., Bigham, M.T., Wheeler, D.S., Devarajan, P., Goldstein, S.L., and Wong, H.R. Identification of candidate serum biomarkers for severe septic shock-associated kidney injury via microarray. Crit Care. 15:R273, 2011.

    Using unsupervised hierarchical clustering, we have identified three subclasses of children with septic shock based exclusively on differential patterns of gene expression. We then interrogated the clinical database and found that one of the three subclasses had a substantially higher level of illness severity, degree of organ failure and mortality, compared to the other two subclasses. Subsequently, the subclass-defining gene signature was distilled to a 100-gene expression signature and depicted using gene expression mosaics that give microarray data a “face” that allows for intuitive pattern recognition (The Gene Expression Dynamics Inspector (GEDI)). Clinicians without formal bioinformatics training were able to reliably allocate patients to the correct subclasses. In a subsequent study, we validated the existence of these clinically relevant subclasses in a formal, separate validation cohort of children with septic shock. We are currently exploring the feasibility of bringing this classification to the bedside in the form of a rapid, clinician-friendly readout.

    Recently, we derived and validated an updated approach to this subclassification method by employing a digital mRNA quantification platform capable of generating actionable data in a time frame that meets the time constraints of decision making in the intensive care unit. This new approach has theranostic implications for critical care medicine.

    The one-hundred subclass-defining genes.

    GEDI mosaics demonstrating the three gene expression-based septic shock subclasses
    GEDI mosaics demonstrating the three gene expression-based septic shock subclasses

    References
    1. Wong, H.R., N.Z. Cvijanovich, N. Anas, G.L. Allen, N.J. Thomas, M.T. Bigham, S.L. Weiss, J. Fitzgerald, P.A. Checchia, K. Meyer, T.P. Shanley, M. Quasney, M. Hall, R. Gedeit, R.J. Freishtat, J. Nowak, R.S. Shekhar, S. Gertz, E. Dawson, K. Howard, K. Harmon, E. Beckman, E. Frank, and C.J. Lindsell. Developing a clinically feasible personalized medicine approach to pediatric septic shock. Am J Respir Crit Care Med. 2015 (in press)
    2. Wong, H.R., Cvijanovich, N.Z., Allen, G.L., Thomas, N.J.,  Freishtat, R.J., Anas, N., Meyer, K., Checchia, P.A., Lin, R., Shanley, T.P., Bigham, M.T., Wheeler, D.S., Doughty, L.A., Tegtmeyer, K., Poynter, S.E., Kaplan, J.M., Chima, R.S., Stalets, E., Basu, R.K., Varisco, B.M. and Barr, F.E. Validation of a gene expression-based subclassification strategy for pediatric septic shock. Crit Care Med. 39:2511-2517, 2011.
    3. Wong, H.R., Wheeler, D.S., Tegtmeyer, K., Poynter, S.E., Kaplan, J.M., Chima, R.S., Stalets, E., Basu, R.K. and Doughty, L.A. Toward a clinically feasible gene expression-based sub-classification strategy for septic shock:  proof of concept. Crit Care Med. 38:1955-1961, 2010.
    4. Wong, H.R., Cvijanovich, N., Lin, R., Allen, G.L., Thomas, N.J., Willson, D.F., Freishtat, R.J., Anas, N., Meyer, K., Checchia, P.A., Monaco, M., Odoms, K. and Shanley, T.P. Identification of pediatric septic shock classes based on genome-wide expression profiling. BMC Medicine. 7:34, 2009.

      We recently identified interleukin-27 (IL-27) as a novel biomarker to predict bacterial infection in critically ill children. IL-27 was discovered using our extensive gene expression database, and in our initial derivation cohort it outperformed procalcitonin, which is currently one of the most widely used clinical biomarkers for infection. We have extended these studies to adults in collaboration with investigators in France and the University of California San Francisco.

      References

      Wong, H.R., K.D. Liu, K.N. Kangelaris, P. Lahni, and C.S. Calfee. Performance of interleukin-27 as a sepsis diagnostic biomarker in critically ill adults. J Crit Care. 29:718-722, 2014.

      Wong, H.R., C.J. Lindsell, P. Lahni, K.W. Hart, and S. Gibot. Interleukin-27 as a sepsis diagnostic biomarker in critically ill adults. Shock. 40:382-386, 2013.

      Wong H.R., N.Z. Cvijanovich, M. Hall, G.L. Allen, N.J. Thomas, R.J. Freishtat, N. Anas, K. Meyer, P.A. Checchia, R. Lin, M.T. Bigham, A. Sen, J. Nowak, M. Quasney, J.W. Henricksen, A. Chopra, S. Banschbach, E. Beckman, K. Harmon, P. Lahni, and T.P. Shanley. Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. Crit Care. 16:R213, 2012.