Modeling probability of additional cases of natalizumab-associated JCV sero-negative progressive multifocal leukoencephalopathy

Abstract

JCV serologic status is used to determine PML risk in natalizumab-treated patients. Given two cases of natalizumab-associated PML in JCV sero-negative patients and two publications that question the false negative rate of the JCV serologic test, clinicians may question whether our understanding of PML risk is adequate. Given that there is no gold standard for diagnosing previous JCV exposure, the test characteristics of the JCV serologic test are unknowable. We propose a model of PML risk in JCV sero-negative natalizumab patients. Using the numbers of JCV sero-positive and -negative patients from a study of PML risk by JCV serologic status (sero-positive: 13,950 and sero-negative: 11,414), we apply a range of sensitivities and specificities in order calculate the number of JCV-exposed but JCV sero-negative patients (false negatives). We then apply a range of rates of developing PML in sero-negative patients to calculate the expected number of PML cases. By using the binomial function, we calculate the probability of a given number of JCV sero-negative PML cases. With this model, one has a means to establish a threshold number of JCV sero-negative natalizumab-associated PML cases at which it is improbable that our understanding of PML risk in JCV sero-negative patients is adequate.