Irene M. Shui

Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink.

BACKGROUND In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009. METHODS Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. RESULTS A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). CONCLUSIONS In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.

Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine.

Background: A pentavalent, bovine-derived rotavirus vaccine (RotaTeq, Merck) was licensed in 2006 for use in infants. A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception. We prospectively evaluated the risk of intussusception and other pre-specified adverse events among RotaTeq recipients in the Vaccine Safety Datalink. Methods: The exposed population included children from age 4 to 48 weeks who received RotaTeq between May 2006 and May 2008. Adverse events over the subsequent 30 days were ascertained from inpatient, outpatient, and emergency department files; cases of intussusception were validated by medical record review. An adaptation of sequential probability ratio testing was employed to compare the cumulative number of observed and expected adverse events on a weekly basis, and a “signal” was generated if the log-likelihood ratio reached a predetermined threshold. This allowed near real-time monitoring to detect selected adverse events. The expected number of cases of intussusception was determined from historical rates in the VSD population. Results: There were 207,621 doses of RotaTeq administered to the study population; 42% were first doses. Five children had computerized diagnosis codes for intussusception, and 6.75 cases were expected based on historical rates (relative risk = 0.74). No elevation in risk was identified for intussusception or any other adverse event. Two of five children with suspected intussusception based on diagnosis codes met the case criteria after medical record review. Conclusions: This study illustrates the feasibility of rapid vaccine safety assessment and provides additional evidence that RotaTeq is not associated with an increased risk of intussusception.

Risk of Intussusception Following Administration of a Pentavalent Rotavirus Vaccine in US Infants

CONTEXT Current rotavirus vaccines were not associated with intussusception in large prelicensure trials. However, recent postlicensure data from international settings suggest the possibility of a low-level elevated risk, primarily in the first week after the first vaccine dose. OBJECTIVE To examine the risk of intussusception following pentavalent rotavirus vaccine (RV5) in US infants. DESIGN, SETTING, AND PATIENTS This cohort study included infants 4 to 34 weeks of age, enrolled in the Vaccine Safety Datalink (VSD) who received RV5 from May 2006-February 2010. We calculated standardized incidence ratios (SIRs), relative risks (RRs), and 95% confidence intervals for the association between intussusception and RV5 by comparing the rates of intussusception in infants who had received RV5 with the rates of intussusception in infants who received other recommended vaccines without concomitant RV5 during the concurrent period and with the expected number of intussusception visits based on background rates assessed prior to US licensure of the RV5 (2001-2005). MAIN OUTCOME MEASURE Intussusception occurring in the 1- to 7-day and 1- to 30-day risk windows following RV5 vaccination. RESULTS During the study period, 786,725 total RV5 doses, which included 309,844 first doses, were administered. We did not observe a statistically significant increased risk of intussusception with RV5 for either comparison group following any dose in either the 1- to 7-day or 1- to 30-day risk window. For the 1- to 30-day window following all RV5 doses, we observed 21 cases of intussusception compared with 20.9 expected cases (SIR, 1.01; 95% CI, 0.62-1.54); following dose 1, we observed 7 cases compared with 5.7 expected cases (SIR, 1.23; 95% CI, 0.5-2.54). For the 1- to 7-day window following all RV5 doses, we observed 4 cases compared with 4.3 expected cases (SIR, 0.92; 95% CI, 0.25-2.36); for dose 1, we observed 1 case compared with 0.8 expected case (SIR, 1.21; 95% CI, 0.03-6.75). The upper 95% CI limit of the SIR (6.75) from the historical comparison translates to an upper limit for the attributable risk of 1 intussusception case per 65,287 RV5 dose-1 recipients. CONCLUSION Among US infants aged 4 to 34 weeks who received RV5, the risk of intussusception was not increased compared with infants who did not receive the rotavirus vaccine.

Vitamin D–Related Genetic Variation, Plasma Vitamin D, and Risk of Lethal Prostate Cancer: A Prospective Nested Case–Control Study

BACKGROUND The association of vitamin D status with prostate cancer is controversial; no association has been observed for overall incidence, but there is a potential link with lethal disease. METHODS We assessed prediagnostic 25-hydroxyvitamin D [25(OH)D] levels in plasma, variation in vitamin D-related genes, and risk of lethal prostate cancer using a prospective case-control study nested within the Health Professionals Follow-up Study. We included 1260 men who were diagnosed with prostate cancer after providing a blood sample in 1993-1995 and 1331 control subjects. Men with prostate cancer were followed through March 2011 for lethal outcomes (n = 114). We selected 97 single-nucleotide polymorphisms (SNPs) in genomic regions with high linkage disequilibrium (tagSNPs) to represent common genetic variation among seven vitamin D-related genes (CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR). We used a logistic kernel machine test to assess whether multimarker SNP sets in seven vitamin D pathway-related genes were collectively associated with prostate cancer. Tests for statistical significance were two-sided. RESULTS Higher 25(OH)D levels were associated with a 57% reduction in the risk of lethal prostate cancer (highest vs lowest quartile: odds ratio = 0.43, 95% confidence interval = 0.24 to 0.76). This finding did not vary by time from blood collection to diagnosis. We found no statistically significant association of plasma 25(OH)D levels with overall prostate cancer. Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer. CONCLUSION In this prospective study, plasma 25(OH)D levels and common variation among several vitamin D-related genes were associated with lethal prostate cancer risk, suggesting that vitamin D is relevant for lethal prostate cancer.

Active Surveillance for Adverse Events: The Experience of the Vaccine Safety Datalink Project

OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) projects experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSDs experience may inform new systems for active safety surveillance.

Attitudes and Beliefs of Parents Concerned About Vaccines: Impact of Timing of Immunization Information

OBJECTIVES: To determine if giving vaccine-information materials before the 2-month vaccination visit to mothers with concerns about vaccine safety positively changed their attitudes and beliefs about vaccine safety. METHODS: Mothers who indicated concerns about infant vaccinations were recruited from 2 separate sites in Tennessee and California and were given vaccine information at 1 of 3 times: during a prenatal visit; a 1-week postpartum well-child visit; or a 2-month vaccination visit. A separate group of concerned mothers was assigned to be followed longitudinally at all 3 time points and was analyzed separately. The mothers reviewed a new vaccine-information pamphlet and Vaccine Information Statements (VIS) from the Centers for Disease Control and Prevention. Attitudes and beliefs about immunization were assessed both before and after the review of materials with written surveys. RESULTS: A total of 272 mothers with immunization concerns participated in the study. After review of the materials, mothers in all groups were significantly more likely to respond positively to questions and statements supporting the safety and importance of vaccines. Mothers who received this information at earlier visits were not significantly more likely to respond positively than mothers who received the information at the childs 2-month vaccination visit; however, participating mothers did indicate a preference for receiving vaccine information before the first vaccination visit. CONCLUSIONS: Distribution of the vaccine-information pamphlet and Vaccine Information Statements significantly improved attitudes about vaccination regardless of at what visit they were provided. Allowing adequate time to review vaccine information, even if done at the vaccination visit, may benefit concerned mothers.

Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer

Insulin‐like growth factor (IGF)−1 is associated with a higher risk of prostate cancer. IGF‐binding protein (IGFBP)−1, a marker for insulin activity, also binds IGF‐1 and inhibits its action. Data on IGFBP‐1 and prostate cancer risk are sparse and whether the IGF and insulin axes interact to affect prostate cancer carcinogenesis is unknown. We evaluated the independent and joint influence of prediagnostic plasma levels of IGFBP‐1 (fasting) and IGF‐1 on risk of prostate cancer among 957 cases and 1,021 controls with fasting levels of IGFBP‐1 and 1,709 cases and 1,778 controls with IGF‐1 nested within the Health Professionals Follow‐up Study. Unconditional logistic regression adjusting for matching factors was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Higher prediagnostic fasting IGFBP‐1 levels were associated with lower risk of prostate cancer (highest vs. lowest quartile OR = 0.67, 95% CI 0.52–0.86, ptrend = 0.003), which remained similar after adjusting for IGF‐1. Prediagnostic IGF‐1 was associated with increased risk of prostate cancer (highest vs. lowest quartile OR = 1.28, 95% CI = 1.05–1.56, ptrend = 0.01). The associations with each marker were primarily driven by lower‐grade and non‐advanced prostate cancer. Being low in IGFBP‐1 and high in IGF‐1 did not confer appreciable additional risk (pinteraction = 0.42). In summary, prediagnostic fasting IGFBP‐1 may influence prostate cancer carcinogenesis. Being low in IGFBP‐1 or high in IGF‐1 is sufficient to elevate the risk of prostate cancer.

Predictive value of seizure ICD-9 codes for vaccine safety research

Post-licensure vaccine safety studies often monitor for seizures using automated screening of ICD-9 codes. This study assessed the positive predictive value (PPV) of ICD-9 codes used to identify seizure visits in children aged 6 weeks to 23 months who were enrolled in seven managed care organizations during January 2000 to December 2005. ICD-9 codes were used to identify visits for seizures in the 0-30-day period following receipt of a pneumococcal vaccine. Visits were stratified by setting of diagnosis (emergency department (ED), outpatient, and inpatient). Review of medical records confirmed whether the visit represented a true acute seizure event. 3233 visits for seizures were identified; 1024 were randomly selected for medical record review and 859 (84%) had records available. The PPV of ICD-9 codes was highest in the ED setting (97%), followed by the inpatient setting (64%). In the outpatient setting, computerized codes for seizures had very low PPV: 16% on days 1-30 following vaccination and 2% for visits on the same day of vaccination. An estimated 77% of true seizures identified were from the ED or inpatient settings. In conclusion, when using ICD-9 codes to identify seizure outcomes, restricting to the ED and inpatient settings of diagnosis may result in less biased preliminary analyses and more efficient vaccine safety studies.

Prostate Cancer (PCa) Risk Variants and Risk of Fatal PCa in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium

BACKGROUND Screening and diagnosis of prostate cancer (PCa) is hampered by an inability to predict who has the potential to develop fatal disease and who has indolent cancer. Studies have identified multiple genetic risk loci for PCa incidence, but it is unknown whether they could be used as biomarkers for PCa-specific mortality (PCSM). OBJECTIVE To examine the association of 47 established PCa risk single-nucleotide polymorphisms (SNPs) with PCSM. DESIGN, SETTING, AND PARTICIPANTS We included 10 487 men who had PCa and 11 024 controls, with a median follow-up of 8.3 yr, during which 1053 PCa deaths occurred. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The main outcome was PCSM. The risk allele was defined as the allele associated with an increased risk for PCa in the literature. We used Cox proportional hazards regression to calculate the hazard ratios of each SNP with time to progression to PCSM after diagnosis. We also used logistic regression to calculate odds ratios for each risk SNP, comparing fatal PCa cases to controls. RESULTS AND LIMITATIONS Among the cases, we found that 8 of the 47 SNPs were significantly associated (p<0.05) with time to PCSM. The risk allele of rs11672691 (intergenic) was associated with an increased risk for PCSM, while 7 SNPs had risk alleles inversely associated (rs13385191 [C2orf43], rs17021918 [PDLIM5], rs10486567 [JAZF1], rs6465657 [LMTK2], rs7127900 (intergenic), rs2735839 [KLK3], rs10993994 [MSMB], rs13385191 [C2orf43]). In the case-control analysis, 22 SNPs were associated (p<0.05) with the risk of fatal PCa, but most did not differentiate between fatal and nonfatal PCa. Rs11672691 and rs10993994 were associated with both fatal and nonfatal PCa, while rs6465657, rs7127900, rs2735839, and rs13385191 were associated with nonfatal PCa only. CONCLUSIONS Eight established risk loci were associated with progression to PCSM after diagnosis. Twenty-two SNPs were associated with fatal PCa incidence, but most did not differentiate between fatal and nonfatal PCa. The relatively small magnitudes of the associations do not translate well into risk prediction, but these findings merit further follow-up, because they may yield important clues about the complex biology of fatal PCa. PATIENT SUMMARY In this report, we assessed whether established PCa risk variants could predict PCSM. We found eight risk variants associated with PCSM: One predicted an increased risk of PCSM, while seven were associated with decreased risk. Larger studies that focus on fatal PCa are needed to identify more markers that could aid prediction.

Community and Patient Values for Preventing Herpes Zoster

ObjectivesThe US Advisory Committee on Immunization Practices has recently recommended a new vaccine against herpes zoster (shingles) for routine use in adults aged ≥60 years. However, estimates of the cost effectiveness of this vaccine vary widely, in part because of gaps in the data on the value of preventing herpes zoster. Our aims were to (i) generate comprehensive information on the value of preventing a range of outcomes of herpes zoster; (ii) compare these values among community members and patients with shingles and post-herpetic neuralgia (PHN); and (iii) identify clinical and demographic characteristics that explain the variation in these values.MethodsCommunity members drawn from a nationally representative survey research panel (n = 527) completed an Internet-based survey using time trade-off and willingness-to-pay questions to value a series of scenarios that described cases of herpes zoster with varying pain intensities (on a scale of 0 to 10, where 0 represents no pain and 10 represents the worst imaginable pain) and duration (30 days to 1 year). Patients with shingles (n = 382) or PHN (n = 137) [defined as having symptoms for =90 days] from two large healthcare systems completed telephone interviews with similar questions to the Internet-based survey and also answered questions about their current experience with herpes zoster. We constructed generalized linear mixed models to evaluate the associations between demographic and clinical characteristics, the length and intensity of the health states and time trade-off and willingness-to-pay values.ResultsIn time trade-off questions, community members offered a mean of 89 (95% CI 24, 182) discounted days to avoid the least severe scenario (pain level of 3 for 1 month) and a mean of 162 (95% CI 88, 259) discounted days to avoid the most severe scenario (pain level of 8 for 12 months). Compared with patients with shingles, community members traded more days to avoid low-severity scenarios but similar numbers of days to avoid high-severity scenarios. Compared with patients with PHN, community members traded fewer days to avoid high-severity scenarios. In multivariate analyses, older age was the only characteristic significantly associated with higher time trade-off values.In willingness-to-pay questions, community members offered a mean of