title: Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility.
abstract: Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional-UMVUE and contrast it with other estimates, including naïve estimators, the well-studied unconditional-UMVUE and the mean and median Whitehead-adjusted estimators. The conditional-UMVUE appears to be a very good choice.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., M2-B500, Seattle, WA 98109, U.S.A. mspepe@u.washington.edu
authors.forename: Margaret Sullivan
authors.initials: MS
authors.lastname: Pepe
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.forename: Gary
authors.initials: G
authors.lastname: Longton
authors.forename: Joseph
authors.initials: J
authors.lastname: Koopmeiners
mesh_terms: D000465:Algorithms; D015982:Bias; D015415:Biomarkers / Q000032:analysis*; D003198:Computer Simulation; D016001:Confidence Intervals; D019937:Diagnostic Techniques and Procedures; D006801:Humans; D015233:Models, Statistical; D009369:Neoplasms / Q000175:diagnosis; D011336:Probability; D018401:Sample Size; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
chemical_list: D015415:Biomarkers