title: Biological variation of thiopurine methyltransferase enzyme activity: when has a significant change taken place?
abstract: BACKGROUND
  Thiopurine methyltransferase (TPMT) enzyme activity is measured before initiating thiopurine therapy to reduce the risk of severe drug-associated myelotoxicity in patients with low enzyme activity. TPMT activity may vary over time in relation to drug treatment and patient clinical condition. What constitutes a significant change in TPMT activity can be derived from biological variation and analytical imprecision.
  
  
  METHODS
  A large national laboratory database was used to identify patients with three or more TPMT activity measurements. Variance of TPMT activity was analysed by determining the total coefficient of variation (CVTOT) of repeated measurements and by correlation with parameters including gender and follow-up time. Between-run analytical imprecision (CVa) was determined by replicate analysis (n = 314).
  
  
  RESULTS
  Of 7383 patients with TPMT measurements, 136 were identified as having three or more measurements over time (range 3-14). Median CVTOT for individual patient results was 14.5% (range 2.5-36.7%). Analytical imprecision (CVa) was 10.3%. A reference change value (or critical difference) with 95% probability was calculated as 42%. Therefore, a change in measured TPMT activity above 42% should lead to considering sources of variation other than biological variation and analytical imprecision.
  
  
  CONCLUSIONS
  TPMT enzyme activity needs to change by at least 42% to determine that a true change has taken place beyond biological variation and analytical imprecision. A single measurement of TPMT activity is sufficient for most clinical purposes.
authors.affiliation: Department of Clinical Pharmacology, Christchurch Hospital, New Zealand.
authors.forename: Remco
authors.initials: R
authors.lastname: van Egmond
authors.forename: Murray L
authors.initials: ML
authors.lastname: Barclay
authors.forename: Paul K L
authors.initials: PK
authors.lastname: Chin
authors.forename: Christiaan W
authors.initials: CW
authors.lastname: Sies
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Florkowski
mesh_terms: D001327:Autoimmune Diseases / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D016208:Databases, Factual; D057075:Enzyme Assays / Q000706:statistics & numerical data*; D004912:Erythrocytes / Q000737:chemistry / Q000201:enzymology*; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D008780:Methyltransferases / Q000097:blood*; D015588:Observer Variation; D011687:Purines / Q000378:metabolism / Q000627:therapeutic use; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D012737:Sex Factors; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000627:therapeutic use
chemical_list: D011687:Purines; D013438:Sulfhydryl Compounds; D008780:Methyltransferases; C022745:thiopurine methyltransferase
keywords: Enzymes; TPMT; analytes; clinical studies; laboratory methods; purine metabolism; quality assurance and control