title: Recombinant human activated protein C for the treatment of severe sepsis and septic shock: a study protocol for incorporating observational evidence using a Bayesian approach.
abstract: BACKGROUND
  Activated protein C (aPC) plays a pivotal role in modulating a severe inflammatory response and is thought to be beneficial for patients with sepsis. However, several meta-analyses of randomised controlled trials (RCTs) show that aPC is not significantly associated with improved survival in critically ill patients with sepsis. One suggestion is that these analyses simply ignored observational evidence. The present study aims to quantitatively demonstrate how observational data can alter the findings derived from synthesised evidence from RCTs by using a Bayesian approach.
  
  
  METHODS
  RCTs and observational studies investigating the effect of aPC on mortality outcome in critically ill patients with sepsis will be included. The quality of included RCTs will be assessed by using the Delphi list. Publication bias will be quantitatively analysed by using the traditional Egger regression test and the Begg rank correlation test. Observational data will be used as the informative prior for the distribution of OR. A power transformation of the observational data likelihood will be considered. Observational evidence will be down-weighted by a power of α which takes values from 0 to 1. Trial sequential analysis will be performed to quantify the reliability of data in meta-analysis adjusting significance levels for sparse data and multiple testing on accumulating trials.
  
  
  BACKGROUND
  PROSPERO (CRD42014009562).
authors.affiliation: Department of Critical Care Medicine, Jinhua Municipal Central Hospital, Jinhua Hospital of Zhejiang University, Zhejiang, PR China.
authors.forename: Zhongheng
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000367:Age Factors; D001499:Bayes Theorem; D017052:Hospital Mortality; D006801:Humans; D064887:Observational Studies as Topic; D011486:Protein C / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D011994:Recombinant Proteins / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D012772:Shock, Septic / Q000188:drug therapy
chemical_list: D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated
keywords: IMMUNOLOGY
references.citation: BMJ Open. 2014 May 23;4(5):e004752
references.pmid: 24860001
references.citation: Biometrics. 1994 Dec;50(4):1088-101
references.pmid: 7786990
references.citation: Crit Care Med. 2010 Oct;38(10 Suppl):S534-8
references.pmid: 21164394
references.citation: J Glob Health. 2012 Jun;2(1):010404
references.pmid: 23198133
references.citation: J Clin Epidemiol. 2008 Oct;61(10):991-6
references.pmid: 18538991
references.citation: Crit Care Med. 2006 Feb;34(2):344-53
references.pmid: 16424713
references.citation: JAMA. 2012 Oct 24;308(16):1651-9
references.pmid: 23093163
references.citation: J Clin Epidemiol. 1998 Dec;51(12):1235-41
references.pmid: 10086815
references.citation: BMJ. 1997 Sep 13;315(7109):629-34
references.pmid: 9310563
references.citation: Circulation. 2008 Sep 16;118(12):1294-303
references.pmid: 18794402
references.citation: JAMA. 2006 Feb 8;295(6):676-80
references.pmid: 16467236
references.citation: J Gen Intern Med. 2008 May;23(5):635-40
references.pmid: 18181004
references.citation: Crit Care Med. 2001 Jul;29(7):1303-10
references.pmid: 11445675
references.citation: J Clin Epidemiol. 2008 Jan;61(1):64-75
references.pmid: 18083463
references.citation: Cochrane Database Syst Rev. 2012 Dec 12;12:CD004388
references.pmid: 23235609
references.citation: Minerva Anestesiol. 2013 Jan;79(1):33-43
references.pmid: 23174922
references.citation: Stat Med. 2001 Feb 28;20(4):641-54
references.pmid: 11223905
references.citation: Lancet Infect Dis. 2012 Sep;12(9):678-86
references.pmid: 22809883
references.citation: Crit Care. 2003 Feb;7(1):1-2
references.pmid: 12617727
references.citation: Stat Med. 2002 Jun 15;21(11):1601-23
references.pmid: 12111922
references.citation: Crit Care Med. 2010 Feb;38(2):367-74
references.pmid: 20035219
references.citation: Stat Methods Med Res. 2001 Aug;10(4):277-303
references.pmid: 11491414
references.citation: Stat Med. 2004 May 15;23(9):1351-75
references.pmid: 15116347
references.citation: Crit Care Med. 2012 Jan;40(1):315-6
references.pmid: 22179356
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Oct 1;305(7):L455-66
references.pmid: 23911436
references.citation: Crit Care. 2012 Feb 06;16(1):107
references.pmid: 22309988