Unmasking in an observational vaccine safety study: Using type 2 diabetes mellitus as an example

In observational vaccine safety studies, diagnosis codes assigned prior to or on the day of vaccination (Day 0) are often excluded from analysis of safety signals since they usually represent pre-existing conditions. The limitations of this approach have been described for autoimmune conditions but not for other chronic conditions. We draw on our experience in a post-licensure quadrivalent human papillomavirus vaccine (HPV4) safety study to examine the effectiveness of exclusion of pre-existing and Day 0 diagnoses of type 2 diabetes mellitus (T2DM) in excluding prevalent T2DM.

Subjects included all 117,402 females ages 9-26 years who received HPV4 August 2006-March 2008 in Kaiser Permanente Southern California. We identified potential incident T2DM cases using ICD9 code 250.xx associated with inpatient and emergency room visits during the 60 days following each HPV4 dose, excluding those with this code prior to their first HPV4 dose. Electronic medical records were reviewed to determine the dates of symptom onset, diagnostic labs, vaccine administration and T2DM diagnosis.

Of 33 potential incident T2DM cases identified using automated data, 4 (12%) were confirmed to have new onset T2DM after medical record review. Nineteen cases were excluded that did not have T2DM or had T2DM diagnosed before Day 0; nine had an abnormal fasting blood sugar (FBS) ordered on Day 0, prompting subsequent evaluation and diagnosis of T2DM; and one had elevated FBS and glucosuria prior to the first dose of HPV4 but T2DM diagnosed at a visit following vaccination.

These results suggest that among adolescents and young adults, the workup and subsequent diagnosis of pre-existing conditions may result from a visit at which a vaccination is administered. This "unmasking" phenomenon is not entirely eliminated by exclusion of pre-existing and Day 0 diagnoses. Medical record review should be considered in the evaluation of potential safety signals.