Missing value imputation in proximity extension assay-based targeted proteomics data.

Targeted proteomics utilizing antibody-based proximity extension assays provides sensitive and highly specific quantifications of plasma protein levels. Multivariate analysis of this data is hampered by frequent missing values (random or left censored), calling for imputation approaches. While appropriate missing-value imputation methods exist, benchmarks of their performance in targeted proteomics data are lacking. Here, we assessed the performance of two methods for imputation of values missing completely at random, the previously top-benchmarked 'missForest' and the recently published 'GSimp' method. Evaluation was accomplished by comparing imputed with remeasured relative concentrations of 91 inflammation related circulating proteins in 86 samples from a cohort of 645 patients with venous thromboembolism. The median Pearson correlation between imputed and remeasured protein expression values was 69.0% for missForest and 71.6% for GSimp (p = 5.8e-4). Imputation with missForest resulted in stronger reduction of variance compared to GSimp (median relative variance of 25.3% vs. 68.6%, p = 2.4e-16) and undesired larger bias in downstream analyses. Irrespective of the imputation method used, the 91 imputed proteins revealed large variations in imputation accuracy, driven by differences in signal to noise ratio and information overlap between proteins. In summary, GSimp outperformed missForest, while both methods show good overall imputation accuracy with large variations between proteins.

Changes of serum interleukin-6 in healthy pregnant women and establishment of relevant reference intervals.

OBJECTIVE: To explore the changes of serum interleukin-6 (IL-6) levels in healthy pregnant women and establish reference intervals (RIs). METHOD: According to the requirements for the RIs study model and the reference population screening criteria in C28-A3 document, Serum IL-6 levels were measured by electrochemiluminescence immunoassay in 480 healthy Chinese women, including 120 pregnant women in each of the first, second and third trimester and 120 non-pregnant women as the negative control. The establishment of RIs for IL-6 were defined using nonparametric percentile. RESULTS: The RIs for serum IL-6 levels in healthy pregnant women is <4.19 pg/ml, the RIs for serum IL-6 levels in healthy pregnant women who are in the first trimester is <3.52 pg/ml, and the RIs for serum IL-6 levels in healthy pregnant women who are in the second and third trimester is <4.40 pg/ml. CONCLUSIONS: Serum IL-6 level in healthy pregnant women is higher than the healthy non-pregnant women, and the level of IL-6 who are in the second and third trimester is higher than those in the first. This paper successfully established RIs for serum IL-6 levels in pregnant women, providing a reference for clinical medical staff and laboratory workers.

Histopathologic and molecular evaluation of the Organ Procurement and Transplantation Network selection criteria for intestinal graft donation.

BACKGROUND: The Organ Procurement and Transplantation Network (OPTN) has formulated criteria for the selection of donors for intestinal transplantation. To date, however, no study has correlated histologic findings of intestinal injury with the OPTN criteria. We aimed to describe histopathologic and molecular features of allograft injury in relation to donor conditions defined by the OPTN criteria. MATERIALS AND METHODS: Graft histology (Park Score), Claudin-3 staining, systemic inflammatory markers (C-reactive protein/lipopolysaccharide-binding protein) and expression of heat shock protein 70, heme oxygenase 1, and interleukin 6 were evaluated in multiorgan deceased donors (donation after brain death [DBD] and donation after cardiac death [DCD]). RESULTS: Ninety-seven samples (52 jejunum/45 ileum) were recovered from 59 donors (46 DBD/13 DCD). The OPTN criterion cold ischemia time correlated with histologic injury (Park score) to which the jejunum appeared more susceptible than the ileum. Claudin-3 staining was higher, and heat shock protein 70 expression lower in donors meeting the OPTN criteria compared with donors not meeting the criteria and in DBD versus DCD. In DBD donors, interleukin 6 expression was higher compared with DCD donors and inversely related to C-reactive protein. CONCLUSIONS: Our multiparameter analysis suggests that the OPTN criteria can be discriminative concerning intestinal graft quality. Our data suggest that DCD intestinal allografts are qualitatively inferior and that the jejunum is more sensitive to ischemia than the ileum.

Efficacy of National Nosocomial Infection Surveillance score, acute-phase proteins, and interleukin-6 for predicting postoperative infections following major gastrointestinal surgery.

CONTEXT AND OBJECTIVE: Postoperative infections should be detected earlier. We investigated the efficacy of the National Nosocomial Infection Surveillance (NNIS) score, interleukin-6 (IL-6) and various acute-phase proteins for predicting postoperative infections. DESIGN AND SETTING: Case series study at the Júlio Müller University Hospital. METHODS: Thirty-two patients who underwent major gastrointestinal procedures between June 2004 and February 2005 were studied. The NNIS score and the evolution of serum IL-6 and various acute-phase proteins (C-reactive protein [CRP], albumin, prealbumin and transferrin) were correlated with postoperative infections and length of hospital stay (LOS). RESULTS: NNIS > 1 (p = 0.01) and low preoperative albumin (p = 0.02) significantly correlated with infection. IL-6 and CRP increased significantly more in patients with infections. Multivariate analysis showed greater risk of infection when NNIS > 1 (odds ratio, OR = 10.66; 95% confidence interval, CI: 1.1-102.0; p = 0.04); preoperative albumin < 3 g/dl (OR = 8.77; 95% CI: 1.13-67.86; p = 0.03); CRP > 30 mg/l on the second postoperative day (OR = 8.27; 95% CI: 1.05-64.79; p = 0.03) and > 12 mg/l on the fifth postoperative day (OR = 25.92; 95% CI: 2.17-332.71; p < 0.01); and IL-6 > 25 pg/ml on the fifth postoperative day (OR = 15.46; 95% CI: 1.19-230.30; p = 0.03). Longer LOS was associated with cancer, transferrin, IL-6 and albumin (p < 0.05). CONCLUSIONS: NNIS, albumin, CRP and IL-6 may be useful as predictive markers for postoperative infections. For predicting LOS, malignant condition, transferrin, albumin and IL-6 are useful.

Extrapolation of experimental safety data to humans: the interleukin-6 case.

Interleukin 6 (IL-6) has a broad spectrum of biological activities, which include stimulation of hemopoiesis, especially thrombopoiesis, of the immune response, proliferation of mesangium cells, and induction of acute-phase proteins in the liver. Therefore, the therapeutic use of IL-6 for any specific clinical indication, e.g., stimulation of thrombopoiesis in severe thrombocytopenia, may be complicated by nonspecific effects. Preclinical experimental investigations of the safety evaluation performed in primates and rodents showed that rhIL-6 is well tolerated. A two- to three-fold increase in thrombocyte counts was observed along with an increase in acute-phase proteins and immunostimulation in the absence of target organ toxicity. Patients receiving rhIL-6, however, had a vigorous acute-phase response, with fever, anemia, and general malaise. Importantly, rhIL-6 administration did not cause mesangioproliferative nephritis or an uncontrolled lymphoproliferation as predicted from IL-6 transgenic mice. Although preclinical investigations are in general quite predictive for humans, safety data should be extrapolated carefully, since important quantitative differences may occur.

The international standard for interleukin-6. Evaluation in an international collaborative study.

Three ampouled preparations of interleukin-6 (IL-6) were evaluated by 12 laboratories in seven countries for their suitability to serve as the international standard of IL-6. The preparations were assayed using in vitro bioassays and immunoassays. On the basis of the results reported here, with the agreement of the participants in the study and with the authorization of the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO) one of the preparations (coded 89/548) was established as the international standard of IL-6.