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Serum microRNA signatures identified by Solexa sequencing predict sepsis patients' mortality: a prospective observational study.

Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie L - PLoS ONE (2012)

Bottom Line: An analysis was done using these seven variables combined.The AUC for these combined variables' predictive probability was 0.953 (95% CI: 0.923-0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712-0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672-0.832), and procalcitonin levels (0.689; 95% CI: 0.611-0.784).With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan Province, China.

ABSTRACT

Background: Sepsis is the leading cause of death in Intensive Care Units. Novel sepsis biomarkers and targets for treatment are needed to improve mortality from sepsis. MicroRNAs (miRNAs) have recently been used as finger prints for sepsis, and our goal in this prospective study was to investigate if serum miRNAs identified in genome-wide scans could predict sepsis mortality.

Methodology/principal findings: We enrolled 214 sepsis patients (117 survivors and 97 non-survivors based on 28-day mortality). Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays was used to test for differences in the levels of miRNAs between survivors and non-survivors. miR-223, miR-15a, miR-16, miR-122, miR-193*, and miR-483-5p were significantly differentially expressed. Receiver operating characteristic curves were generated and the areas under the curve (AUC) for these six miRNAs for predicting sepsis mortality ranged from 0.610 (95%CI: 0.523-0.697) to 0.790 (95%CI: 0.719-0.861). Logistic regression analysis showed that sepsis stage, Sequential Organ Failure Assessment scores, Acute Physiology and Chronic Health Evaluation II scores, miR-15a, miR-16, miR-193b*, and miR-483-5p were associated with death from sepsis. An analysis was done using these seven variables combined. The AUC for these combined variables' predictive probability was 0.953 (95% CI: 0.923-0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712-0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672-0.832), and procalcitonin levels (0.689; 95% CI: 0.611-0.784). With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%. Additionally, miR-193b* had the highest odds ratio for sepsis mortality of 9.23 (95% CI: 1.20-71.16).

Conclusion/significance: Six serum miRNA's were identified as prognostic predictors for sepsis patients.

Trial registration: ClinicalTrials.gov NCT01207531.

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Related in: MedlinePlus

Comparison of 12 miRNAs expression levels between sepsis non-survivors and survivors in a validation set.Differentially expressed miRNAs identified by Solexa sequencing were validated by qRT-PCR in sepsis survivors (S; N = 15) compared to non-survivors (D; N = 15). MiR-16 (p = 0.005), miR-15a (p = 0.021), miR-223 (p = 0.015), miR-483-5p (p<0.001), miR-193b* (p<0.001), miR-122 (p<0.001), and miR-499-5p (p = 0.006) were significantly different after validation with qRT-PCR. Expression levels of the 12 miRNAs were normalized to U6 snRNA above normal controls and given as fold-changes (2–ΔΔCt ). △△Ct  =  (CtmiRNA-CtU6snRNA) patients-(CtmiRNA-CtU6 snRNA)controls. Mann-Whitney U-test was used for statistical comparisons.
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pone-0038885-g001: Comparison of 12 miRNAs expression levels between sepsis non-survivors and survivors in a validation set.Differentially expressed miRNAs identified by Solexa sequencing were validated by qRT-PCR in sepsis survivors (S; N = 15) compared to non-survivors (D; N = 15). MiR-16 (p = 0.005), miR-15a (p = 0.021), miR-223 (p = 0.015), miR-483-5p (p<0.001), miR-193b* (p<0.001), miR-122 (p<0.001), and miR-499-5p (p = 0.006) were significantly different after validation with qRT-PCR. Expression levels of the 12 miRNAs were normalized to U6 snRNA above normal controls and given as fold-changes (2–ΔΔCt ). △△Ct  =  (CtmiRNA-CtU6snRNA) patients-(CtmiRNA-CtU6 snRNA)controls. Mann-Whitney U-test was used for statistical comparisons.

Mentions: We used qRT-PCR to validate the altered expressions of the 12 candidate miRNAs for 15 survivors and 15 non-survivors. After validation, seven miRNAs were identified (associated p-values in parentheses): miR-223 (p = 0.015); miR-15a (p = 0.005); miR-16 (p = 0.021); miR-499-5p (p = 0.006); miR-122 (p<0.001), miR-193b*(p<0.001) and miR-483-5p (p<0.001). Compared to the surviving group, miR-16 and miR-223 were up-regulated in the non-surviving group and the levels of miR-15a, miR-499-5p, miR-193b*, miR-122, and miR-483-5p were up-regulated (Figure 1). Although levels of miR-15b were not significantly different in the validation set, previous study has proved that levels of miR-15b were significantly higher than other expressed miRNAs in T cell subsets [23]. Hence, miR-15b was also selected for further confirmation.


Serum microRNA signatures identified by Solexa sequencing predict sepsis patients' mortality: a prospective observational study.

Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie L - PLoS ONE (2012)

Comparison of 12 miRNAs expression levels between sepsis non-survivors and survivors in a validation set.Differentially expressed miRNAs identified by Solexa sequencing were validated by qRT-PCR in sepsis survivors (S; N = 15) compared to non-survivors (D; N = 15). MiR-16 (p = 0.005), miR-15a (p = 0.021), miR-223 (p = 0.015), miR-483-5p (p<0.001), miR-193b* (p<0.001), miR-122 (p<0.001), and miR-499-5p (p = 0.006) were significantly different after validation with qRT-PCR. Expression levels of the 12 miRNAs were normalized to U6 snRNA above normal controls and given as fold-changes (2–ΔΔCt ). △△Ct  =  (CtmiRNA-CtU6snRNA) patients-(CtmiRNA-CtU6 snRNA)controls. Mann-Whitney U-test was used for statistical comparisons.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3376145&req=5

pone-0038885-g001: Comparison of 12 miRNAs expression levels between sepsis non-survivors and survivors in a validation set.Differentially expressed miRNAs identified by Solexa sequencing were validated by qRT-PCR in sepsis survivors (S; N = 15) compared to non-survivors (D; N = 15). MiR-16 (p = 0.005), miR-15a (p = 0.021), miR-223 (p = 0.015), miR-483-5p (p<0.001), miR-193b* (p<0.001), miR-122 (p<0.001), and miR-499-5p (p = 0.006) were significantly different after validation with qRT-PCR. Expression levels of the 12 miRNAs were normalized to U6 snRNA above normal controls and given as fold-changes (2–ΔΔCt ). △△Ct  =  (CtmiRNA-CtU6snRNA) patients-(CtmiRNA-CtU6 snRNA)controls. Mann-Whitney U-test was used for statistical comparisons.
Mentions: We used qRT-PCR to validate the altered expressions of the 12 candidate miRNAs for 15 survivors and 15 non-survivors. After validation, seven miRNAs were identified (associated p-values in parentheses): miR-223 (p = 0.015); miR-15a (p = 0.005); miR-16 (p = 0.021); miR-499-5p (p = 0.006); miR-122 (p<0.001), miR-193b*(p<0.001) and miR-483-5p (p<0.001). Compared to the surviving group, miR-16 and miR-223 were up-regulated in the non-surviving group and the levels of miR-15a, miR-499-5p, miR-193b*, miR-122, and miR-483-5p were up-regulated (Figure 1). Although levels of miR-15b were not significantly different in the validation set, previous study has proved that levels of miR-15b were significantly higher than other expressed miRNAs in T cell subsets [23]. Hence, miR-15b was also selected for further confirmation.

Bottom Line: An analysis was done using these seven variables combined.The AUC for these combined variables' predictive probability was 0.953 (95% CI: 0.923-0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712-0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672-0.832), and procalcitonin levels (0.689; 95% CI: 0.611-0.784).With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%.

View Article: PubMed Central - PubMed

Affiliation: Department of Respiratory Medicine, Hainan Branch of Chinese PLA General Hospital, Sanya, Hainan Province, China.

ABSTRACT

Background: Sepsis is the leading cause of death in Intensive Care Units. Novel sepsis biomarkers and targets for treatment are needed to improve mortality from sepsis. MicroRNAs (miRNAs) have recently been used as finger prints for sepsis, and our goal in this prospective study was to investigate if serum miRNAs identified in genome-wide scans could predict sepsis mortality.

Methodology/principal findings: We enrolled 214 sepsis patients (117 survivors and 97 non-survivors based on 28-day mortality). Solexa sequencing followed by quantitative reverse transcriptase polymerase chain reaction assays was used to test for differences in the levels of miRNAs between survivors and non-survivors. miR-223, miR-15a, miR-16, miR-122, miR-193*, and miR-483-5p were significantly differentially expressed. Receiver operating characteristic curves were generated and the areas under the curve (AUC) for these six miRNAs for predicting sepsis mortality ranged from 0.610 (95%CI: 0.523-0.697) to 0.790 (95%CI: 0.719-0.861). Logistic regression analysis showed that sepsis stage, Sequential Organ Failure Assessment scores, Acute Physiology and Chronic Health Evaluation II scores, miR-15a, miR-16, miR-193b*, and miR-483-5p were associated with death from sepsis. An analysis was done using these seven variables combined. The AUC for these combined variables' predictive probability was 0.953 (95% CI: 0.923-0.983), which was much higher than the AUCs for Acute Physiology and Chronic Health Evaluation II scores (0.782; 95% CI: 0.712-0.851), Sequential Organ Failure Assessment scores (0.752; 95% CI: 0.672-0.832), and procalcitonin levels (0.689; 95% CI: 0.611-0.784). With a cut-off point of 0.550, the predictive value of the seven variables had a sensitivity of 88.5% and a specificity of 90.4%. Additionally, miR-193b* had the highest odds ratio for sepsis mortality of 9.23 (95% CI: 1.20-71.16).

Conclusion/significance: Six serum miRNA's were identified as prognostic predictors for sepsis patients.

Trial registration: ClinicalTrials.gov NCT01207531.

Show MeSH
Related in: MedlinePlus