Prognostic and predictive enrichment in sepsis.
Ontology highlight
ABSTRACT:
SUBMITTER: Stanski NL
PROVIDER: S-EPMC7097452 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Prognostic and predictive enrichment in sepsis.
Stanski Natalja L NL Wong Hector R HR
Nature reviews. Nephrology 20190911 1
Sepsis is a heterogeneous disease state that is both common and consequential in critically ill patients. Unfortunately, the heterogeneity of sepsis at the individual patient level has hindered advances in the field beyond the current therapeutic standards, which consist of supportive care and antibiotics. This complexity has prompted attempts to develop a precision medicine approach, with research aimed towards stratifying patients into more homogeneous cohorts with shared biological features, ...[more]
Similar Datasets
Project description:BACKGROUND:Enrichment strategies improve therapeutic targeting and trial efficiency, but enrichment factors for sepsis trials are lacking. We determined whether concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1), interleukin-8 (IL8), and angiopoietin-2 (Ang2) could identify sepsis patients at higher mortality risk and serve as prognostic enrichment factors. METHODS:In a multicenter prospective cohort study of 400 critically ill septic patients, we derived and validated thresholds for each marker and expressed prognostic enrichment using risk differences (RD) of 30-day mortality as predictive values. We then used decision curve analysis to simulate the prognostic enrichment of each marker and compare different prognostic enrichment strategies. MEASUREMENTS AND MAIN RESULTS:An admission sTNFR1 concentration?>?8861?pg/ml identified patients with increased mortality in both the derivation (RD 21.6%) and validation (RD 17.8%) populations. Among immunocompetent patients, an IL8 concentration?>?94?pg/ml identified patients with increased mortality in both the derivation (RD 17.7%) and validation (RD 27.0%) populations. An Ang2 level?>?9761?pg/ml identified patients at 21.3% and 12.3% increased risk of mortality in the derivation and validation populations, respectively. Using sTNFR1 or IL8 to select high-risk patients improved clinical trial power and efficiency compared to selecting patients with septic shock. Ang2 did not outperform septic shock as an enrichment factor. CONCLUSIONS:Thresholds for sTNFR1 and IL8 consistently identified sepsis patients with higher mortality risk and may have utility for prognostic enrichment in sepsis trials.
| S-EPMC6902425 | biostudies-literature
Project description:BackgroundSepsis is a heterogenous syndrome and individualized management strategy is the key to successful treatment. Genome wide expression profiling has been utilized for identifying subclasses of sepsis, but the clinical utility of these subclasses was limited because of the classification instability, and the lack of a robust class prediction model with extensive external validation. The study aimed to develop a parsimonious class model for the prediction of class membership and validate the model for its prognostic and predictive capability in external datasets.MethodsThe Gene Expression Omnibus (GEO) and ArrayExpress databases were searched from inception to April 2020. Datasets containing whole blood gene expression profiling in adult sepsis patients were included. Autoencoder was used to extract representative features for k-means clustering. Genetic algorithms (GA) were employed to derive a parsimonious 5-gene class prediction model. The class model was then applied to external datasets (n = 780) to evaluate its prognostic and predictive performance.FindingsA total of 12 datasets involving 1613 patients were included. Two classes were identified in the discovery cohort (n = 685). Class 1 was characterized by immunosuppression with higher mortality than class 2 (21.8% [70/321] vs. 12.1% [44/364]; p < 0.01 for Chi-square test). A 5-gene class model (C14orf159, AKNA, PILRA, STOM and USP4) was developed with GA. In external validation cohorts, the 5-gene class model (AUC: 0.707; 95% CI: 0.664 - 0.750) performed better in predicting mortality than sepsis response signature (SRS) endotypes (AUC: 0.610; 95% CI: 0.521 - 0.700), and performed equivalently to the APACHE II score (AUC: 0.681; 95% CI: 0.595 - 0.767). In the dataset E-MTAB-7581, the use of hydrocortisone was associated with increased risk of mortality (OR: 3.15 [1.13, 8.82]; p = 0.029) in class 2. The effect was not statistically significant in class 1 (OR: 1.88 [0.70, 5.09]; p = 0.211).InterpretationOur study identified two classes of sepsis that showed different mortality rates and responses to hydrocortisone therapy. Class 1 was characterized by immunosuppression with higher mortality rate than class 2. We further developed a 5-gene class model to predict class membership.FundingThe study was funded by the National Natural Science Foundation of China (Grant No. 81,901,929).
| S-EPMC7658497 | biostudies-literature
Project description:Microvascular dysfunctions are associated with poor prognosis in sepsis. However, the potential role of clinical assessment of peripheral ischemic microvascular reserve (PIMR), a parameter that characterizes the variation of peripheral perfusion index (PPI) after brief ischemia of the upper arm, as a tool to detect sepsis-induced microvascular dysfunction and for prognostic enrichment has not been established. To address this gap, this study investigated the association of high PIMR with mortality over time in patients with sepsis and its subgroups (with and without shock) and peripheral perfusion (capillary-refill time). This observational cohort study enrolled consecutive septic patients in four Intensive-care units. After fluid resuscitation, PIMR was evaluated using the oximetry-derived PPI and post-occlusive reactive hyperemia for two consecutive days in septic patients. Two hundred and twenty-six patients were included-117 (52%) in the low PIMR group and 109 (48%) in the high PIMR group. The study revealed differences in mortality between groups on the first day, which was higher in the high PIMR group (RR 1.25; 95% CI 1.00-1.55; p = 0.04) and maintained its prognostic significance after multivariate adjustment. Subsequently, this analysis was made for sepsis subgroups and showed significant differences in mortality only for the septic-shock subgroup, with was higher in the high PIMR group (RR 2.14; 95% CI 1.49-3.08; p = 0.01). The temporal ΔPPI peak values (%) analyses did not demonstrate maintenance of the predictive value over the first 48 h in either group (p > 0.05). A moderate positive correlation (r = 0.41) between ΔPPI peak (%) and capillary-refill time (s) was found within the first 24 hours of diagnosis (p < 0.001). In conclusion, detecting a high PIMR within 24 h appears to be a prognostic marker for mortality in sepsis. Furthermore, its potential as a prognostic enrichment tool seems to occur mainly in septic shock.
| S-EPMC10321605 | biostudies-literature
Project description:Colorectal cancer (CRC) is the third most commonly diagnosed cancer in both men and women in the United States, with an estimated 153,760 new cases predicted for 2007. Since the 1960s, 5-fluorouracil (5-FU) has remained the mainstay of therapeutic options in the treatment of advanced CRC, with response rates of 20% to 25%. The introduction of newer agents such as oxaliplatin and irinotecan in combination with 5-FU has increased response rates to 40% to 50% in advanced disease and improved overall survival. The development of monoclonal antibodies targeting the epidermal growth factor receptor or vascular endothelial growth factor has demonstrated additional clinical benefit for patients with metastatic disease. However, many patients succumb to their disease, and a significant proportion will experience severe chemotherapy-associated toxicities while deriving little or no benefit. To improve the treatment of CRC, efforts must be directed toward the identification of patients who are likely to respond to a specific therapy, those who will experience severe toxicities, and those who will benefit from chemotherapy in the adjuvant setting. However, the utility of individual markers of response, toxicity, and disease recurrence remains in question. Efforts are now under way to develop multimarker profiles that can more accurately predict disease response. In this review, we discuss both predictive and prognostic markers identified in the treatment of CRC in terms of their robustness and their ability to assist the clinician in developing the most efficacious and least toxic therapeutic strategy for each patient.
| S-EPMC2631215 | biostudies-other
Project description:BackgroundThe revised definition of sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection (SEPSIS-3). The objective of this study was to evaluate procalcitonin (PCT) for the diagnosis and prognosis of sepsis using SEPSIS-3.MethodsWe enrolled 248 patients, who were admitted to the emergency department with suspected bacterial infection from June 2016 to February 2017. Definite bacterial infection was defined by proven culture results, and probable bacterial infection was based on diagnostic modalities other than culture. The sequential organ failure assessment (SOFA) score of 2 points or more from the baseline was diagnosed as sepsis. PCT was measured by the AFIAS-6 immunoassay system (Boditech Med Inc.) using whole blood. White blood cell (WBC), C-reactive protein (CRP), and erythrocyte sedimentation rate (ERS) were evaluated.ResultsThe final diagnosis was sepsis in 185 patients with infection of respiratory and genitourinary tract constituted 84.6%. The area under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI) was as follows: PCT, 0.682 (0.589-0.765); CRP, 0.583 (0.487-0.673); ESR, 0.540 (0.515-0.699); and WBC, 0.611 (0.455-0.633), respectively. In multivariate analysis, age, SOFA, and PCT (log scale) predicted non-survivors with an odds ratio with 95% confidence interval of 1.055 (1.008-1.105), 1.303 (1.142-1.486), and 2.004 (1.240-3.238), respectively. Among sepsis group, initial PCT was increased in non-survivor (23.2 ng/dL) compared to survivor group (8.1 ng/dL) with statistical significance (P = .005).ConclusionsPCT could support and predict the unfavorable prognosis of sepsis based on SEPSIS-3, whereas diagnostic potential of PCT requires further evaluations.
| S-EPMC6868407 | biostudies-literature
Project description:This prospective observational study explored the predictive value of CD86 in the early diagnosis of sepsis in the emergency department. The primary endpoint was the factors associated with a diagnosis of sepsis. The secondary endpoint was the factors associated with mortality among patients with sepsis. It enrolled inpatients with infection or high clinical suspicion of infection in the emergency department of a tertiary Hospital between September 2019 and June 2021. The patients were divided into the sepsis and non-sepsis groups according to the Sepsis-3 standard. The non-sepsis group included 56 patients, and the sepsis group included 65 patients (19 of whom ultimately died). The multivariable analysis showed that CD86% (odds ratio [OR] = 1.22, 95% confidence interval [CI]: 1.04-1.44, P = 0.015), platelet count (OR = 0.99, 95%CI: 0.986-0.997, P = 0.001), interleukin-10 (OR = 1.01, 95%CI: 1.004-1.025, P = 0.009), and procalcitonin (OR = 1.17, 95%CI: 1.01-1.37, P = 0.043) were independent risk factors for sepsis, while human leukocyte antigen (HLA%) (OR = 0.96, 05%CI: 0.935-0.995, P = 0.022), respiratory rate (OR = 1.16, 95%CI: 1.03-1.30, P = 0.014), and platelet count (OR = 1.01, 95%CI: 1.002-1.016, P = 0.016) were independent risk factors for death in patients with sepsis. The model for sepsis (CD86%, platelets, interleukin-10, and procalcitonin) and the model for death (HLA%, respiratory rate, and platelets) had an area under the curve (AUC) of 0.870 and 0.843, respectively. CD86% in the first 24 h after admission for acute infection was independently associated with the occurrence of sepsis in the emergency department.
| S-EPMC11008888 | biostudies-literature
Project description:Oncology indispensably leads us to personalized medicine, which allows an individual approach to be taken with each patient. Personalized oncology is based on pharmacogenomics and the effect of genetic differences in individuals (germline and somatic) on the way cancer patients respond to chemotherapeutics. Biomarkers detected using molecular biology tools allow the molecular characterization of cancer signatures and provide information relevant for personalized treatment. Biomarkers can be divided into two main subgroups: prognostic and predictive. The aim of the application of prognostic biomarkers, which provide information on the overall cancer outcome in patients, is to facilitate cancer diagnosis, usually with no need for putting invasive methods into use. Predictive biomarkers help to optimize therapy decisions, as they provide information on the likelihood of response to a given chemotherapeutic. Among the prognostic factors that identify patients with different outcome risks (e.g., recurrence of the disease), the following factors can be distinguished: somatic and germline mutations, changes in DNA methylation that lead to the enhancement or suppression of gene expression, the occurrence of elevated levels of microRNA (miRNA) capable of binding specific messenger RNA (mRNA) molecules, which affects gene expression, as well as the presence of circulating tumor cells (CTCs) in blood, which leads to a poor prognosis for the patient. Biomarkers for personalized oncology are used mainly in molecular diagnostics of chronic myeloid leukemia, colon, breast and lung cancer, and recently in melanoma. They are successfully used in the evaluation of the benefits that can be achieved through targeted therapy or in the evaluation of toxic effects of the chemotherapeutic used in the therapy.
| S-EPMC4031398 | biostudies-other
Project description:Gliomas are the most common central nervous system tumors. New technologies, including genetic research and advanced statistical methods, revolutionize the therapeutic approach to the patient and reveal new points of treatment options. Moreover, the 2021 World Health Organization Classification of Tumors of the Central Nervous System has fundamentally changed the classification of gliomas and incorporated many molecular biomarkers. Given the rapid progress in neuro-oncology, here we compile the latest research on prognostic and predictive biomarkers in gliomas. In adult patients, IDH mutations are positive prognostic markers and have the greatest prognostic significance. However, CDKN2A deletion, in IDH-mutant astrocytomas, is a marker of the highest malignancy grade. Moreover, the presence of TERT promoter mutations, EGFR alterations, or a combination of chromosome 7 gain and 10 loss upgrade IDH-wildtype astrocytoma to glioblastoma. In pediatric patients, H3F3A alterations are the most important markers which predict the worse outcome. MGMT promoter methylation has the greatest clinical significance in predicting responses to temozolomide (TMZ). Conversely, mismatch repair defects cause hypermutation phenotype predicting poor response to TMZ. Finally, we discussed liquid biopsies, which are promising diagnostic, prognostic, and predictive techniques, but further work is needed to implement these novel technologies in clinical practice.
| S-EPMC8508830 | biostudies-literature
Project description:BackgroundIn sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity.MethodsIn this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion.Results32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38-5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61-4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56-2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12-0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55-0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64-0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74-0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64-0.97), and a specificity of 0.96 (95%-CI 0.88-0.99).ConclusionsThe combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.
| S-EPMC11246358 | biostudies-literature
Project description:ObjectiveTo evaluate the prognostic performance of the Pediatric Index of Mortality 2 (PIM2), ferritin, lactate, C-reactive protein (CRP), and leukocytes, alone and in combination, in pediatric patients with sepsis admitted to the pediatric intensive care unit (PICU).MethodsA retrospective study was conducted in a PICU in Brazil. All patients aged 6 months to 18 years admitted with a diagnosis of sepsis were eligible for inclusion. Those with ferritin and C-reactive protein measured within 48h and lactate and leukocytes within 24h of admission were included in the prognostic performance analysis.ResultsOf 350 eligible patients with sepsis, 294 had undergone all measurements required for analysis and were included in the study. PIM2, ferritin, lactate, and CRP had good discriminatory power for mortality, with PIM2 and ferritin being superior to CRP. The cutoff values for PIM2 (> 14%), ferritin (> 135ng/mL), lactate (> 1.7mmol/L), and CRP (> 6.7mg/mL) were associated with mortality. The combination of ferritin, lactate, and CRP had a positive predictive value of 43% for mortality, similar to that of PIM2 alone (38.6%). The combined use of the three biomarkers plus PIM2 increased the positive predictive value to 76% and accuracy to 0.945.ConclusionsPIM2, ferritin, lactate, and CRP alone showed good prognostic performance for mortality in pediatric patients older than 6 months with sepsis. When combined, they were able to predict death in three-fourths of the patients with sepsis. Total leukocyte count was not useful as a prognostic marker.
| S-EPMC9432292 | biostudies-literature