title: Calculation of limits for significant bidirectional changes in two or more serial results of a biomarker based on a computer simulation model.
abstract: BACKGROUND
  Reference change values provide objective tools to assess the significance of a change in two consecutive results of a biomarker from an individual. However, in practice, more results are usually available and using the reference change value concept on more than two results will increase the number of false positive results.
  
  
  METHODS
  A computer simulation model was developed using Excel. Based on 10,000 simulated measurements among healthy individuals, a series of up to 20 results of a biomarker from each individual was generated using different values for the within-subject biological variation plus the analytical variation. Each new result in this series was compared to the initial result. These successive serial differences were computed to give limits for significant bidirectional changes with constant cumulated maximum probabilities of 95% (p < 0.05) and 99% (p < 0.01).
  
  
  RESULTS
  From an individual factors used to multiply the first result were calculated to create limits for constant cumulated significant changes. The factors were shown to become a function of the number of results included and the total coefficient of variation.
  
  
  CONCLUSIONS
  The first result should be multiplied by the appropriate factors for increase and decrease to give the limits for a significant bidirectional change in several consecutive measurements.
authors.affiliation: Department of Clinical Biochemistry, North Zealand Hospital, University of Copenhagen, Hillerød, Denmark Flemming.Lund@regionh.dk.
authors.forename: Flemming
authors.initials: F
authors.lastname: Lund
authors.affiliation: Department of Clinical Biochemistry, North Zealand Hospital, University of Copenhagen, Hillerød, Denmark Norwegian Quality Improvement of Primary Care Laboratories (NOKLUS), Section for General Practice, University of Bergen, Bergen, Norway.
authors.forename: Per Hyltoft
authors.initials: PH
authors.lastname: Petersen
authors.affiliation: Centre for Research into Cancer Prevention and Screening, University of Dundee, Dundee, Scotland.
authors.forename: Callum G
authors.initials: CG
authors.lastname: Fraser
authors.affiliation: Department of Clinical Biochemistry, North Zealand Hospital, University of Copenhagen, Hillerød, Denmark.
authors.forename: György
authors.initials: G
authors.lastname: Sölétormos
mesh_terms: D000465:Algorithms; D015415:Biomarkers / Q000032:analysis*; D002624:Chemistry, Clinical / Q000379:methods*; D003198:Computer Simulation; D006801:Humans; D015233:Models, Statistical; D016011:Normal Distribution; D012016:Reference Values; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers
keywords: False positives; initial concentration; log-normal (Gaussian) distribution; monitoring; normal (Gaussian) distribution; reference change values