Statistical approaches using longitudinal biomarkers for disease early detection: A comparison of methodologies

• Published in: Statistics in medicine Vol. 39; no. 29; pp. 4405 - 4420
• Main Authors: Han, Yongli, Albert, Paul S., Berg, Christine D., Wentzensen, Nicolas, Katki, Hormuzd A., Liu, Danping
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 20.12.2020
• Subjects: Algorithms; Biomarkers; Biomarkers, Tumor; CA-125 Antigen; Calibration; Disease; disease early detection; Early Detection of Cancer; Female; Humans; Male; Medical screening; Ovarian cancer; Ovarian Neoplasms - diagnosis; pattern mixture model; risk of ovarian cancer algorithm; ROC Curve; shared random effects model; time‐dependent AUC; disease early detection; pattern mixture model; risk of ovarian cancer algorithm; time-dependent AUC; shared random effects model
• ISSN: 0277-6715; 1097-0258; 1097-0258
• DOI: 10.1002/sim.8731

Early detection of clinical outcomes such as cancer may be predicted using longitudinal biomarker measurements. Tracking longitudinal biomarkers as a way to identify early disease onset may help to reduce mortality from diseases like ovarian cancer that are more treatable if detected early. Two disease risk prediction frameworks, the shared random effects model (SREM) and the pattern mixture model (PMM) could be used to assess longitudinal biomarkers on disease early detection. In this article, we studied the discrimination and calibration performances of SREM and PMM on disease early detection through an application to ovarian cancer, where early detection using the risk of ovarian cancer algorithm (ROCA) has been evaluated. Comparisons of the above three approaches were performed via analyses of the ovarian cancer data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Discrimination was evaluated by the time‐dependent receiver operating characteristic curve and its area, while calibration was assessed using calibration plot and the ratio of observed to expected number of diseased subjects. The out‐of‐sample performances were calculated via using leave‐one‐out cross‐validation, aiming to minimize potential model overfitting. A careful analysis of using the biomarker cancer antigen 125 for ovarian cancer early detection showed significantly improved discrimination performance of PMM as compared with SREM and ROCA, nevertheless all approaches were generally well calibrated. Robustness of all approaches was further investigated in extensive simulation studies. The improved performance of PMM relative to ROCA is in part due to the fact that the biomarker measurements were taken at a yearly interval, which is not frequent enough to reliably estimate the changepoint or the slope after changepoint in cases under ROCA.