Statistical methods to correct for verification bias in diagnostic studies are inadequate when there are few false negatives: a simulation study

<p>Abstract</p> <p>Background</p> <p>A common feature of diagnostic research is that results for a diagnostic gold standard are available primarily for patients who are positive for the test under investigation. Data from such studies are subject to what has been termed "verification bias". We evaluated statistical methods for verification bias correction when there are few false negatives.</p> <p>Methods</p> <p>A simulation study was conducted of a screening study subject to verification bias. We compared estimates of the area-under-the-curve (AUC) corrected for verification bias varying both the rate and mechanism of verification.</p> <p>Results</p> <p>In a single simulated data set, varying false negatives from 0 to 4 led to verification bias corrected AUCs ranging from 0.550 to 0.852. Excess variation associated with low numbers of false negatives was confirmed in simulation studies and by analyses of published studies that incorporated verification bias correction. The 2.5^th– 97.5^thcentile range constituted as much as 60% of the possible range of AUCs for some simulations.</p> <p>Conclusion</p> <p>Screening programs are designed such that there are few false negatives. Standard statistical methods for verification bias correction are inadequate in this circumstance.</p

Declining recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting

Introduction: Randomized trials indicate that adjuvant radiotherapy plus tamoxifen decrease the five-year risk of recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery from about 20% to 8%. The aims of this study were to examine the use and impact of these therapies on risk of recurrence among ductal carcinoma in situ patients diagnosed and treated in the community setting. Methods: We identified 2,995 patients diagnosed with ductal carcinoma in situ between 1990 and 2001 and treated with breast-conserving surgery at three large health plans. Medical charts were reviewed to confirm diagnosis and treatment and to obtain information on subsequent breast cancers. On a subset of patients, slides from the index ductal carcinoma in situ were reviewed for histopathologic features. Cumulative incidence curves were generated and Cox regression was used to examine changes in five-year risk of recurrence across diagnosis years, with and without adjusting for trends in use of adjuvant therapies. Results: Use of radiotherapy increased from 25.8% in 1990-1991 to 61.3% in 2000-2001; tamoxifen increased from 2.3% to 34.4%. A total of 245 patients had a local recurrence within five years of their index ductal carcinoma in situ. The five-year risk of any local recurrence decreased from 14.3% (95% confidence interval 9.8 to 18.7) for patients diagnosed in 1990-1991 to 7.7% (95% confidence interval 5.5 to 9.9) for patients diagnosed in 1998-1999; invasive recurrence decreased from 7.0% (95% confidence interval 3.8 to 10.3) to 3.1% (95% confidence interval 1.7 to 4.6). In Cox models, the association between diagnosis year and risk of recurrence was modestly attenuated after accounting for use of adjuvant therapy. Between 1990-1991 and 2000-2001, the proportion of patients with tumors with high nuclear grade decreased from 46% to 32% (P = 0.03) and those with involved surgical margins dropped from 15% to 0% (P = 0.03). Conclusions: The marked increase in the 1990s in the use of adjuvant therapy for ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting only partially explains the 50% decline in risk of recurrence. Changes in pathology factors have likely also contributed to this decline

Yersinia enterocolitica Serum Resistance Proteins YadA and Ail Bind the Complement Regulator C4b-Binding Protein

Many pathogens are equipped with factors providing resistance against the bactericidal action of complement. Yersinia enterocolitica, a Gram-negative enteric pathogen with invasive properties, efficiently resists the deleterious action of human complement. The major Y. enterocolitica serum resistance determinants include outer membrane proteins YadA and Ail. Lipopolysaccharide (LPS) O-antigen (O-ag) and outer core (OC) do not contribute directly to complement resistance. The aim of this study was to analyze a possible mechanism whereby Y. enterocolitica could inhibit the antibody-mediated classical pathway of complement activation. We show that Y. enterocolitica serotypes O:3, O:8, and O:9 bind C4b-binding protein (C4bp), an inhibitor of both the classical and lectin pathways of complement. To identify the C4bp receptors on Y. enterocolitica serotype O:3 surface, a set of mutants expressing YadA, Ail, O-ag, and OC in different combinations was tested for the ability to bind C4bp. The studies showed that both YadA and Ail acted as C4bp receptors. Ail-mediated C4bp binding, however, was blocked by the O-ag and OC, and could be observed only with mutants lacking these LPS structures. C4bp bound to Y. enterocolitica was functionally active and participated in the factor I-mediated degradation of C4b. These findings show that Y. enterocolitica uses two proteins, YadA and Ail, to bind C4bp. Binding of C4bp could help Y. enterocolitica to evade complement-mediated clearance in the human host

Evaluation of Urine CCA Assays for Detection of Schistosoma mansoni Infection in Western Kenya

Although accurate assessment of the prevalence of Schistosoma mansoni is important for the design and evaluation of control programs, the most widely used tools for diagnosis are limited by suboptimal sensitivity, slow turn-around-time, or inability to distinguish current from former infections. Recently, two tests that detect circulating cathodic antigen (CCA) in urine of patients with schistosomiasis became commercially available. As part of a larger study on schistosomiasis prevalence in young children, we evaluated the performance and diagnostic accuracy of these tests—the carbon test strip designed for use in the laboratory and the cassette format test intended for field use. In comparison to 6 Kato-Katz exams, the carbon and cassette CCA tests had sensitivities of 88.4% and 94.2% and specificities of 70.9% and 59.4%, respectively. However, because of the known limitations of the Kato-Katz assay, we also utilized latent class analysis (LCA) incorporating the CCA, Kato-Katz, and schistosome-specific antibody results to determine their sensitivities and specificities. The laboratory-based CCA test had a sensitivity of 91.7% and a specificity of 89.4% by LCA while the cassette test had a sensitivity of 96.3% and a specificity of 74.7%. The intensity of the reaction in both urine CCA tests reflected stool egg burden and their performance was not affected by the presence of soil transmitted helminth infections. Our results suggest that urine-based assays for CCA may be valuable in screening for S. mansoni infections