title: Quantitation of intrathecal immunoglobulin synthesis - a new empirical formula.
abstract: OBJECTIVE
  Intrathecal immunoglobulin (Ig) synthesis occurs in various chronic inflammatory neurological diseases. Different formulae have been developed for quantitative determination of Ig synthesis within the cerebrospinal fluid (CSF) compartment. The hyperbolic formula of Reiber is frequently used which, however, returns a considerable number of false positive results in empirical observations.
  
  
  METHODS
  A computerized database of more than 19 000 paired CSF and serum samples was screened for patients presumed negative for local Ig synthesis and a new formula characterizing this collective was calculated. The validity of this formula was confirmed by several validation steps.
  
  
  RESULTS
  A cohort of 1173 patients with normal CSF findings was used for quantile regression. The 97.5th quantile of the formula Qlim(IgX)=a×Qalbb was considered as the cut-off curve for intrathecal Ig synthesis using different constants a and b for IgG, IgA and IgM. Compared to the Reiber formula, a lower level of false positive results was produced especially for IgM and IgA which was confirmed in a separate clinically well defined validation cohort. In 77 patients with discrepant findings between Reiber and our formula no specific diagnoses were found confirming the low diagnostic value of borderline Ig synthesis.
  
  
  CONCLUSIONS
  A new approximation formula was developed for determination of intrathecal Ig synthesis which produces fewer false positive results without reducing diagnostic sensitivity.
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Auer
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Hegen
authors.affiliation: Department of Statistics, Faculty of Economics and Statistics, University Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Zeileis
authors.affiliation: Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: F
authors.identifier: http://orcid.org/0000-0003-4541-8841
authors.initials: F
authors.lastname: Deisenhammer
mesh_terms: D000328:Adult; D000368:Aged; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis*; D002623:Chemistry Techniques, Analytical / Q000592:standards*; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis* / Q000097:blood / Q000134:cerebrospinal fluid*; D008297:Male; D008875:Middle Aged; D012680:Sensitivity and Specificity
chemical_list: D002556:Cerebrospinal Fluid Proteins; D007136:Immunoglobulins
keywords: cerebrospinal fluid; formula; immunoglobulins; intrathecal synthesis