Abstract
Multiple different recombinant and peptide antigens are now available for serodiagnosis of Lyme disease (LD), but optimizing test utilization remains challenging. Since 1995 the Centers for Disease Control and Prevention (CDC) has recommended a 2-tiered serologic approach consisting of a first-tier whole-cell enzyme immunoassay (EIA) for polyvalent antibodies to Borrelia burgdorferi followed by confirmation of positive or equivocal results by IgG and IgM immunoblots [standard 2-tiered (STT) approach]. Newer modified 2-tiered (MTT) approaches employ a second-tier EIA to detect antibodies to B. burgdorferi rather than immunoblotting. We applied modern bioinformatic techniques to a large public database of recombinant and peptide antigen-based immunoassays to improve testing strategy. A retrospective CDC collection of 280 LD samples and 559 controls had been tested using the STT approach as well as kinetic-EIAs for VlsE1-IgG, C6-IgG, VlsE1-IgM, and pepC10-IgM antibodies. When used individually, the cutoff for each kinetic-EIA was set to generate 99% specificity. Utilizing logistic-likelihood regression analysis and receiver operating characteristic (ROC) techniques we determined that VlsE1-IgG, C6-IgG, and pepC10-IgM antibodies each contributed significant diagnostic information; a single-tier diagnostic score (DS) was generated for each sample using a weighted linear combination of antibody levels to these 3 antigens. DS performance was then compared to the STT and to MTT models employing different combinations of kinetic-EIAs. After setting the DS cutoff to match STT specificity (99%), the DS was 22.5% more sensitive than the STT for early-acute-phase disease (95% CI: 11.8% to 32.2%), 16.0% more sensitive for early-convalescent-phase disease (95% CI: 7.2% to 24.7%), and equivalent for detection of disseminated infection. The DS was also significantly more sensitive for early-acute-phase LD than MTT models whose specificity met or exceeded 99%. Prospective validation of this single-tier diagnostic score for Lyme disease will require larger studies using a broader range of potential cross-reacting conditions.
Highlights
Lyme disease (LD) is the most common tick-borne disease in the United States and constitutes an increasing public health threat; the Centers for Disease Control and Prevention (CDC) estimates that 476,000 Americans are diagnosed and treated yearly [1]
We re-evaluated this same database to explore multi-antibody diagnostic scores and modified 2-tiered approaches not previously reported; our results demonstrated that diagnostic scores performed significantly better than standard 2-tiered approach (STT) and MTT approaches for diagnosis of early LD
Logistic-likelihood regression analysis was performed using the entire dataset; Table 1 details the beta-coefficients and standard errors generated for VlsE1-IgG, C6-IgG, pepC10-IgM, VlsE1-IgM antibodies by kinetic-enzyme immunoassay (EIA) and antibodies to whole-cell lysate by VIDAS EIA
Summary
Lyme disease (LD) is the most common tick-borne disease in the United States and constitutes an increasing public health threat; the CDC estimates that 476,000 Americans are diagnosed and treated yearly [1]. Measuring serum antibodies to Borrelia burgdorferi, the causative agent, is the most common diagnostic approach for disseminated infection. Since 1995 the CDC has advocated a 2-tiered serologic method consisting of a first-tier EIA or immunofluorescent antibody assay (using either whole-cell or B. burgdorferi-derived peptide antigens), followed by IgG and IgM Western blot confirmation of positive or equivocal first-tier results [3]. While at least 90% sensitive for late-stage disease [4], the standard 2-tiered approach (STT) is limited by low sensitivity for early LD (38% to 50%) and false-positives secondary to subjective interpretation of IgM immunoblot bands and cross-reacting antibodies (1% to 8%) [4,5,6,7]; these drawbacks have led to a search for more sensitive and specific alternatives
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