Standardization of Diagnostic Biomarker Concentrations in Urine: The Hematuria Caveat

Cherith N. Reid, Michael Stevenson, Funso Abogunrin, Mark W. Ruddock, Frank Emmert-Streib, John V. Lamont, Kate E. Williamson

    Research output: Contribution to journalArticleScientificpeer-review

    23 Citations (Scopus)

    Abstract

    Sensitive and specific urinary biomarkers can improve patient outcomes in many diseases through informing early diagnosis. Unfortunately, to date, the accuracy and translation of diagnostic urinary biomarkers into clinical practice has been disappointing. We believe this may be due to inappropriate standardization of diagnostic urinary biomarkers. Our objective was therefore to characterize the effects of standardizing urinary levels of IL-6, IL-8, and VEGF using the commonly applied standards namely urinary creatinine, osmolarity and protein. First, we report results based on the biomarker levels measured in 120 hematuric patients, 80 with pathologically confirmed bladder cancer, 27 with confounding pathologies and 13 in whom no underlying cause for their hematuria was identified, designated "no diagnosis". Protein levels were related to final diagnostic categories (p = 0.022, ANOVA). Osmolarity (mean = 529 mOsm; median = 528 mOsm) was normally distributed, while creatinine (mean = 10163 μmol/l, median = 9350 μmol/l) and protein (0.3297, 0.1155 mg/ml) distributions were not. When we compared AUROCs for IL-6, IL-8 and VEGF levels, we found that protein standardized levels consistently resulted in the lowest AUROCs. The latter suggests that protein standardization attenuates the "true" differences in biomarker levels across controls and bladder cancer samples. Second, in 72 hematuric patients; 48 bladder cancer and 24 controls, in whom urine samples had been collected on recruitment and at follow-up (median = 11 (1 to 20 months)), we demonstrate that protein levels were approximately 24% lower at follow-up (Bland Altman plots). There was an association between differences in individual biomarkers and differences in protein levels over time, particularly in control patients. Collectively, our findings identify caveats intrinsic to the common practice of protein standardization in biomarker discovery studies conducted on urine, particularly in patients with hematuria.

    Original languageEnglish
    Article numbere53354
    JournalPLoS ONE
    Volume7
    Issue number12
    DOIs
    Publication statusPublished - 31 Dec 2012
    Publication typeA1 Journal article-refereed

    ASJC Scopus subject areas

    • General Agricultural and Biological Sciences
    • General Biochemistry,Genetics and Molecular Biology
    • General Medicine

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