APPLICATION OF RELIABILITY MODELS TO STUDIES OF BIOMARKER VALIDATION

We present a model of biomarker validation developed in our laboratory , the results of the validation study, and the impact of the estimatio n of the variance components on the design of future molecular epidemi ologic studies. Four different biomarkers of exposure are illustrated: Dna-protein cross-link (DNA-PC), DNA-amino acid cross link (DNA-AA), metallothionein gene expression (MT), and autoantibodies to oxidized D NA bases (DNAox). The general scheme for the validation experiments in volves n subjects measured on k occasions, with j replicate samples an alyzed on each occasion. Multiple subjects, occasions, and replicates provide information on intersubject, intrasubject, and analytical meas urement variability, respectively. The analysis of variance showed a s ignificant effect of batch variability for DNA-PC and MT gene expressi on, whereas DNAox showed a significant between-subject variability. Am ong the amino acids tested, cysteine and methionine showed a significa nt contribution of both batch and between-subject variability, threoni ne showed between-subject variability only, and tyrosine showed betwee n-batch and between-subject variability. The total variance estimated through the experiment was used to calculate the minimum sample size r equired for a future epidemiologic study including the same biomarkers used for the reliability study. Such validation studies can detect th e various components of variability of a biomarker and indicate needed improvements of an assay, along with possible use in field studies.