Ursula Garczarek

Improved Diagnosis of Colorectal Cancer Using a Combination of Fecal Occult Blood and Novel Fecal Protein Markers

BACKGROUND & AIMS Annual testing for fecal occult blood is recommended as first-line screening for the detection of colorectal cancer (CRC), but is affected by limited sensitivity. We initiated a proteomics-based search for novel biomarkers to improve the sensitivity of detection of CRC in stool samples. METHODS Six markers, including immunologic fecal occult blood test (iFOBT), were evaluated in a collective of 551 samples (186 CRC, 113 advanced adenoma, and 252 control patients) to establish the diagnostic performance of each marker and marker combinations. RESULTS We tested the known stool markers hemoglobin (iFOBT), hemoglobin-haptoglobin, calprotectin, carcinoembryogenic antigen, and the novel fecal markers tissue inhibitor of metalloproteinase-1 (TIMP-1) and S100A12. The best diagnostic performance was found for S100A12 with an area under the curve of 0.95, followed by TIMP-1 (0.92), hemoglobin-haptoglobin (0.92), hemoglobin (0.91), calprotectin (0.90), and carcinoembryogenic antigen (0.66). By using Bayes logistic regression as a mathematic model, the highest sensitivity (88%) for the detection of CRC at 95% specificity was obtained with the marker pair S100A12 and hemoglobin-haptoglobin. Increasing the specificity to 98%, the combination of S100A12, hemoglobin-haptoglobin, and TIMP-1 resulted in a sensitivity of 82%, with the highest increase of sensitivity found in early tumor stages (international union against cancer stage I: 74% sensitivity vs 57% of the best single marker). CONCLUSIONS Depending on the specificity selected, a marker pair, S100A12 and hemoglobin-haptoglobin, or a triple combination including TIMP-1, allowed the detection of CRC at significantly higher rates than can be obtained with iFOBT alone.

Diagnosis of rheumatoid arthritis: multivariate analysis of biomarkers

Abstract Objective. To test if a combination of biomarkers can increase the classification power of autoantibodies to cyclic citrullinated peptides (anti-CCP) in the diagnosis of rheumatoid arthritis (RA) depending on the diagnostic situation. Methods. Biomarkers were subject to three inclusion/exclusion criteria (discrimination between RA patients and healthy blood donors, ability to identify anti-CCP-negative RA patients, specificity in a panel with major non-rheumatological diseases) before univariate ranking and multivariate analysis was carried out using a modelling panel (n=906). To enable the evaluation of the classification power in different diagnostic settings the disease controls (n=542) were weighted according to the admission rates in rheumatology clinics modelling a clinic panel or according to the relative prevalences of musculoskeletal disorders in the general population seen by general practitioners modelling a GP panel. Results. Out of 131 biomarkers considered originally, we evaluated 32 biomarkers in this study, of which only seven passed the three inclusion/exclusion criteria and were combined by multivariate analysis using four different mathematical models. In the modelled clinic panel, anti-CCP was the lead marker with a sensitivity of 75.8% and a specificity of 94.0%. Due to the lack in specificity of the markers other than anti-CCP in this diagnostic setting, any gain in sensitivity by any marker combination is off-set by a corresponding loss in specificity. In the modelled GP panel, the best marker combination of anti-CCP and interleukin (IL)-6 resulted in a sensitivity gain of 7.6% (85.9% vs. 78.3%) at a minor loss in specificity of 1.6% (90.3% vs. 91.9%) compared with anti-CCP as the best single marker. Conclusions. Depending on the composition of the sample panel, anti-CCP alone or anti-CCP in combination with IL-6 has the highest classification power for the diagnosis of established RA.