title: Limitations of bi-linear regression analysis for the determination of receptor occupancy with positron emission tomography.
abstract: OBJECTIVE
  Linear/multilinear regression methods are widely used in quantitative neuroreceptor positron emission tomography. A reference tissue method based on a bi-linear operational equation, the bi-linear reference tissue method, has been introduced in order to overcome the need for arterial blood sampling. The aim of the present paper was to investigate the sensitivity of the bi-linear reference tissue method to statistical noise, with special regard to the assessment of receptor occupancy. In addition, improvement of the bi-linear reference tissue method by regularization using physiological constraints was evaluated.
  
  
  METHODS
  Application of the bi-linear method to dynamic positron emission tomography using the serotonin transporter ligand C-(+)McN5652 was considered. Investigations were performed by computer simulations and analysis of 29 patient studies.
  
  
  RESULTS
  The equilibrium specific-to-non-specific partition coefficient V"3 was significantly underestimated by the bi-linear reference tissue method. At realistic noise levels the extent of the underestimation ranged from 25% to 75% for partition coefficients ranging from 0.3 to 0.3, respectively. This caused a 15-60% underestimation of changes in receptor occupancy after simulated intervention. The noise dependence of the bias was confirmed in the patient studies. Regularization significantly reduced the underestimation of the occupancy.
  
  
  CONCLUSIONS
  When receptor status or noise level vary substantially, as in receptor occupancy studies, the bias of the bi-linear reference tissue method should be taken into account.
authors.affiliation: Department of Nuclear Medicine, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. buchert@uke.uni-hamburg.de
authors.forename: Ralph
authors.initials: R
authors.lastname: Buchert
authors.forename: József
authors.initials: J
authors.lastname: Varga
authors.forename: Janos
authors.initials: J
authors.lastname: Mester
mesh_terms: D000328:Adult; D000465:Algorithms; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D007546:Isoquinolines / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D011984:Sensory Receptor Cells / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013788:Thalamus / Q000000981:diagnostic imaging* / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D007546:Isoquinolines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C058079:McN 5652