Biomarkers for use in prognosis of mortality in critically ill patients

Abstract

Biomarkers and methods of using them for aiding diagnosis, prognosis, and treatment of critically ill patients are disclosed. In particular, the invention relates to the use of biomarkers for prognosis of mortality in critically ill patients with sepsis, severe trauma, or burns.

1 - 38 . (canceled) 
     
     
         39 . A method for treating a critically ill patient, comprising:
 (a) measuring the expression levels of two or more biomarkers in a biological sample obtained from a subject;   (b) calculating a composite biomarker value using the expression levels;   (c) determining that the composite biomarker value exceeds a threshold value; and   (d) administering organ support or an immunomodulatory therapy to the patient.   
     
     
         40 . The method of  claim 39 , wherein the two or more biomarkers comprise at least three biomarkers. 
     
     
         41 . The method of  claim 39 , wherein the two or more biomarkers are selected from DEFA4, CD163, PER1, RGS1, HIF1A, SEPP1, C11orf74, CIT, LY86, TST, OR52R1, KCNJ2, CTSG, and MPO. 
     
     
         42 . The method of  claim 41 , wherein the measuring comprises measuring the mRNA expression levels of the two or more biomarkers. 
     
     
         43 . The method of  claim 39 , wherein the expression levels of the two or more biomarkers are increased compared to reference value ranges for the two or more biomarkers, wherein the reference value ranges are derived from one or more patients that do not have critical illness requiring ICU admission. 
     
     
         44 . The method of  claim 39 , wherein the expression levels of the two or more biomarkers are decreased compared to reference value ranges for the two or more biomarkers, wherein the reference value ranges are derived from one or more patients that do not have critical illness requiring ICU admission. 
     
     
         45 . The method of  claim 39 , wherein the composite biomarker is determined by a computer comprising a processing unit using a formula based on the expression levels of the two or more biomarkers. 
     
     
         46 . The method of  claim 39 , wherein the composite biomarker has been validated in multiple cohorts, wherein the multiple cohorts comprise at least one discovery cohort from which the composite biomarker value was derived and at least one validation cohort fully independent from the at least one discovery cohort. 
     
     
         47 . The method of  claim 46 , wherein the at least one discovery cohort and the at least one validation cohort compare hospitalized patient who do not progress to ICU admission or mortality within 30 days to those that do progress to ICU admission or mortality within 30 days. 
     
     
         48 . The method of  claim 46 , wherein the at least one validation cohort comprises at least three independent cohorts and has at least 200 samples in total. 
     
     
         49 . The method of  claim 46 , wherein the at least one validation cohort comprises at least five independent cohorts and has at least 500 samples in total. 
     
     
         50 . The method of  claim 47 , wherein the hospitalized patients are sepsis, trauma, or burn patients. 
     
     
         51 . The method of  claim 50 , wherein the hospitalized patients comprise patients within 48 hours of admission. 
     
     
         52 . The method of  claim 39 , wherein the two or more biomarkers are differentially expressed between patients who require ICU-level care within 7 days, and those who do not. 
     
     
         53 . The method of  claim 46 , wherein an area under the receiver operating characteristic (ROC) curve for the composite biomarker is at least 0.75 in the at least one validation cohort. 
     
     
         54 . The method of  claim 46 , wherein the average area under the receiver operating characteristic (ROC) curve for the composite biomarker across all available validation cohorts is at least 0.75 
     
     
         55 . The method of  claim 46 , wherein an area under the receiver operating characteristic (ROC) curve for the composite biomarker is at least 0.84 in the at least one validation cohort. 
     
     
         56 . The method of  claim 46 , wherein the average area under the receiver operating characteristic (ROC) curve for the composite biomarker across all available validation cohorts is at least 0.84. 
     
     
         57 . The method of  claim 39 , wherein the biological sample comprises a whole blood, a buffy coat, a plasma, a serum, a urine, a saliva, a tissue biopsy, a peripheral blood mononucleated cell (PBMC), a band cell, a neutrophil, a monocyte, a T cell, or a combination thereof. 
     
     
         58 . The method of  claim 39 , wherein the measuring comprises microarray analysis, polymerase chain reaction (PCR), quantitative PCR (qPCR), reverse transcriptase polymerase chain reaction (RT_PCR), isothermal amplification, Northern blot, serial analysis of gene expression (SAGE), CRISPR, or amplification-free RNA capture. 
     
     
         59 . The method of  claim 39 , further comprising admitting the subject to a hospital. 
     
     
         60 . A kit for performing the method of  claim 39 .