title: Mixed-effects modeling of clinical DCE-MRI data: application to colorectal liver metastases treated with bevacizumab.
abstract: OBJECTIVE
  Most dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data are evaluated for individual patients with cohorts analyzed to detect significant changes from baseline values, repeating the process at each posttreatment timepoint. Our study aimed to develop a statistically valid model for the complete time course of DCE-MRI data in a patient cohort.
  
  
  METHODS
  Data from 10 patients with colorectal cancer liver metastases were analyzed, including two baseline scans and four post-bevacizumab scans. Apparent changes in tumor median K(trans) were adjusted for changes in observed enhancing tumor fraction (EnF) by multiplying K(trans) by EnF (KEnF). A mixed-effects model (MEM) was defined to describe the KEnF time course for all patients simultaneously by assuming a three-parameter indirect response model with model parameters lognormally distributed across patients.
  
  
  RESULTS
  The typical cohort time course showed a KEnF reduction to 59% of baseline at 24 hours, returning to 65% of baseline values by day 12. Interpatient variability of model parameters ranged from 11% to 307%.
  
  
  CONCLUSIONS
  The MEM approach has potential for comparing responses at a group level in clinical trials with different doses, schedules, or combination regimens. Furthermore, the KEnF biomarker successfully resolved confounds in interpreting K(trans) arising from therapy induced changes in the volume of enhancing tumor.
authors.affiliation: Department of Pharmacokinetics & Pharmacodynamics, Genentech, Inc., South San Francisco, California, USA.
authors.forename: Gregory Z
authors.initials: GZ
authors.lastname: Ferl
authors.forename: James P B
authors.initials: JP
authors.lastname: O'Connor
authors.forename: Geoffrey J M
authors.initials: GJ
authors.lastname: Parker
authors.forename: Richard A D
authors.initials: RA
authors.lastname: Carano
authors.forename: Shiv J
authors.initials: SJ
authors.lastname: Acharya
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Jayson
authors.forename: Ruediger E
authors.initials: RE
authors.lastname: Port
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000068258:Bevacizumab; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000473:pathology*; D003287:Contrast Media; D005260:Female; D019786:Gadolinium DTPA; D006801:Humans; D007089:Image Enhancement; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003287:Contrast Media; D000068258:Bevacizumab; C064925:gadodiamide; D019786:Gadolinium DTPA
keywords: DCE-MRI; bevacizumab; biomarker; colorectal liver metastases