Combining markers with and without the limit of detection.

In this paper, we consider the combination of markers with and without the limit of detection (LOD). LOD is often encountered when measuring proteomic markers. Because of the limited detecting ability of an equipment or instrument, it is difficult to measure markers at a relatively low level. Suppose that after some monotonic transformation, the marker values approximately follow multivariate normal distributions. We propose to estimate distribution parameters while taking the LOD into account, and then combine markers using the results from the linear discriminant analysis. Our simulation results show that the ROC curve parameter estimates generated from the proposed method are much closer to the truth than simply using the linear discriminant analysis to combine markers without considering the LOD. In addition, we propose a procedure to select and combine a subset of markers when many candidate markers are available. The procedure based on the correlation among markers is different from a common understanding that a subset of the most accurate markers should be selected for the combination. The simulation studies show that the accuracy of a combined marker can be largely impacted by the correlation of marker measurements. Our methods are applied to a protein pathway dataset to combine proteomic biomarkers to distinguish cancer patients from non-cancer patients.

Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study.

Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without.

Randomized Control Trial on the Effectiveness of Collagen Cross-linking on Bullous Keratopathy.

PURPOSE: To investigate the long-term effect and safety of collagen cross-linking (CXL) on patients with bullous keratopathy (BK) in a randomized control manner. It is, to our knowledge, the first randomized control study on the effect of CXL on BK. METHODS: Subjects were randomized to receive CXL as in the standard protocol for treating keratoconus or a placebo treatment. Subjects were assessed at baseline and up to 12 months after treatment. Primary outcomes were central corneal thickness (CCT) and pain scores. RESULTS: Forty-two patients with BK participated in the study treatment, 26 subjects were randomized to the CXL group and 16 subjects to the control group. The reduction of CCT in the CXL group was 37.6 and 63.8 µm at 2 and 4 weeks, respectively, which were significantly higher than that in the control group. However, there was no statistical difference in CCT reduction between the 2 groups at 12 weeks and after. There were no consistent advantages in pain score, corneal clarity, and visual acuity over the controls throughout the 1-year follow-up. However, CXL was associated with more recurrent epithelial defect (12%), and 2 of the 3 subjects with epithelial defect required amniotic membrane transplant. CONCLUSIONS: CXL reduced corneal thickness in the patients with BK, at least for the initial period. However, there were no improvement in pain, corneal clarity, and vision that were of more clinical relevance to the patients. Its short-term benefit was unlikely to outweigh its potential risk of recurrent epithelial defect.