title: Management and interpretation of heterogeneous observational data: using insulin-like growth factor-I data from the NordiNet® International Outcome Study.
abstract: OBJECTIVE
  The NordiNet® International Outcome Study (IOS), a large-scale, non-interventional, multi-centre, real-world study of Norditropin® treatment, registers insulin-like growth factor-I (IGF-I) values, as measured by different assays. This paper considers the potential biases introduced by using a single IGF-I reference data set in analysing NordiNet® IOS data.
  
  
  METHODS
  To evaluate possible biases from different IGF-I assays used across NordiNet® IOS, a mixed-effect linear model was fitted to IGF-I data (analyses on log-transformed data). Pre-growth hormone treatment (pre-GHT) IGF-I values were assumed to depend on diagnosis, sex and age. During GHT, a treatment-effect dependent on these factors was added. Differences between assays were assumed multiplicative on the original scale. Individual measurements were scaled to a common level (Nichols Advantage) giving adjusted IGF-I standard deviation score (SDS) values.
  
  
  RESULTS
  In total, 49 495 IGF-I measurements were available from 9481 paediatric patients. Mixed-effect linear modelling showed a systematic difference between IGF-I levels measured by different assays. Differences were minimised when assessing change in IGF-I SDS from the start of GHT to 1-year follow-up. This applied to values adjusted for actual-assay used and for unadjusted delta IGF-I SDS values. Largest differences between unadjusted change in IGF-I SDS values were: for growth hormone deficiency 0.1 (girls) and 0.3 (boys); for small-for-gestational age 0.1; and for Turner syndrome 0.2. Similar magnitude differences were seen for data with unknown assay.
  
  
  CONCLUSIONS
  Analysis and modelling suggest the current approach to IGF-I data collection and analyses in the NordiNet® IOS is sound: in a large cohort without assay-used information, potential bias is minimised by analysing changes in IGF-I SDS.
authors.affiliation: Institute for Experimental Paediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address: Oliver.Blankenstein@charite.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: Blankenstein
authors.affiliation: Epidemiology, Novo Nordisk A/S, Søborg, Denmark. Electronic address: bitp@novonordisk.com.
authors.forename: Birgitte Tønnes
authors.initials: BT
authors.lastname: Pedersen
authors.affiliation: Global Medical Affairs Biopharm, Novo Nordisk Health Care AG, Zurich, Switzerland. Electronic address: mslp@novonordisk.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Schlumpf
authors.affiliation: StatGroup ApS, Copenhagen, Denmark. Electronic address: aha@statgroup.dk.
authors.forename: Arne Haahr
authors.initials: AH
authors.lastname: Andreasen
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway. Electronic address: Petur.Juliusson@k2.uib.no.
authors.forename: Pétur Benedikt
authors.initials: PB
authors.lastname: Júlíusson
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006130:Growth Disorders / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007018:Hypopituitarism / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007118:Immunoassay / Q000592:standards; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D017063:Outcome Assessment, Health Care; D012015:Reference Standards; D014424:Turner Syndrome / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
chemical_list: C583557:IGF1 protein, human; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I
keywords: Assay; Growth hormone; Growth hormone therapy; IGF-I; Norditropin®; Pharmacoepidemiology