title: Validation of a model-based virtual trials method for tight glycemic control in intensive care.
abstract: BACKGROUND
  In-silico virtual patients and trials offer significant advantages in cost, time and safety for designing effective tight glycemic control (TGC) protocols. However, no such method has fully validated the independence of virtual patients (or resulting clinical trial predictions) from the data used to create them. This study uses matched cohorts from a TGC clinical trial to validate virtual patients and in-silico virtual trial models and methods.
  
  
  METHODS
  Data from a 211 patient subset of the Glucontrol trial in Liege, Belgium. Glucontrol-A (N = 142) targeted 4.4-6.1 mmol/L and Glucontrol-B (N = 69) targeted 7.8-10.0 mmol/L. Cohorts were matched by APACHE II score, initial BG, age, weight, BMI and sex (p > 0.25). Virtual patients are created by fitting a clinically validated model to clinical data, yielding time varying insulin sensitivity profiles (SI(t)) that drives in-silico patients.Model fit and intra-patient (forward) prediction errors are used to validate individual in-silico virtual patients. Self-validation (tests A protocol on Group-A virtual patients; and B protocol on B virtual patients) and cross-validation (tests A protocol on Group-B virtual patients; and B protocol on A virtual patients) are used in comparison to clinical data to assess ability to predict clinical trial results.
  
  
  RESULTS
  Model fit errors were small (<0.25%) for all patients, indicating model fitness. Median forward prediction errors were: 4.3, 2.8 and 3.5% for Group-A, Group-B and Overall (A+B), indicating individual virtual patients were accurate representations of real patients. SI and its variability were similar between cohorts indicating they were metabolically similar.Self and cross validation results were within 1-10% of the clinical data for both Group-A and Group-B. Self-validation indicated clinically insignificant errors due to model and/or clinical compliance. Cross-validation clearly showed that virtual patients enabled by identified patient-specific SI(t) profiles can accurately predict the performance of independent and different TGC protocols.
  
  
  CONCLUSIONS
  This study fully validates these virtual patients and in silico virtual trial methods, and clearly shows they can accurately simulate, in advance, the clinical results of a TGC protocol, enabling rapid in silico protocol design and optimization. These outcomes provide the first rigorous validation of a virtual in-silico patient and virtual trials methodology.
authors.affiliation: Dept. of Mechanical Engoneering, Centre for Bio-Engineering, University of Canterbury, Christchurch, New Zealand. geoff.chase@canterbury.ac.nz
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Chase
authors.forename: Fatanah
authors.initials: F
authors.lastname: Suhaimi
authors.forename: Sophie
authors.initials: S
authors.lastname: Penning
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Preiser
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Le Compte
authors.forename: Jessica
authors.initials: J
authors.lastname: Lin
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Pretty
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Shaw
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Moorhead
authors.forename: Thomas
authors.initials: T
authors.lastname: Desaive
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000378:metabolism*; D002986:Clinical Trials as Topic; D015331:Cohort Studies; D003422:Critical Care / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D014584:User-Computer Interface
chemical_list: D001786:Blood Glucose