Tools and Links

Pediatrics
May 2011, VOLUME 127 / ISSUE Supplement 1
Vaccine-Safety System and Vaccine-Safety Studies

The Vaccine Safety Datalink: A Model for Monitoring Immunization Safety

James Baggs, Julianne Gee, Edwin Lewis, Gabrielle Fowler, Patti Benson, Tracy Lieu, Allison Naleway, Nicola P. Klein, Roger Baxter, Edward Belongia, Jason Glanz, Simon J. Hambidge, Steven J. Jacobsen, Lisa Jackson, Jim Nordin, Eric Weintraub
Download PDF

Abstract

The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.

High vaccination coverage has significantly reduced vaccine-preventable disease morbidity and mortality worldwide, especially among children.1,2 Vaccines are generally regarded as safe and effective; however, serious adverse events following immunization (AEFI) can occur.3,4 Although vaccine safety is rigorously assessed during prelicensing clinical trials, sample sizes are not adequate to detect rare adverse events, long-term adverse events are not examined, and populations are not heterogenous.3 In recent years, public concerns about the safety of vaccines have grown significantly.5 Immunization-safety programs are an important component of maintaining the public trust in our national immunization program.5 Close monitoring of vaccine safety also protects the public's health and contributes to safer vaccines and vaccination practices.

In 1990, the Centers for Disease Control and Prevention (CDC) National Immunization Program created the Vaccine Safety Datalink (VSD) project to conduct postmarketing evaluations of vaccine safety.6,7 Initially, the project used medical event and demographic information from ∼6 million children younger than 6 years for VSD research from 4 participating managed care organizations (MCOs): Group Health Cooperative of Puget Sound (GHC) (Seattle, WA); Kaiser Permanente Northwest (NWK) (Portland, OR); Kaiser Permanente of Northern California (KPNC) (Oakland, CA); and Kaiser Permanente of Southern California (Los Angeles, CA).6,–,9 Later, vaccine-safety studies were conducted to include children younger than 18 years at all 4 sites and adults 18 years of age and older at GHC, KPNC, and NWK. In 2001, 4 additional MCOs joined the VSD, and during the last 7 years the VSD has made other changes to enhance its ability to serve as the primary mechanism for population-based evaluations of vaccine safety in the United States. The VSD is part of the CDC Immunization Safety Office. The Immunization Safety Office also includes the Vaccine Adverse Event Reporting System (VAERS), the Clinical Immunization Safety Assessment Network, and the Brighton Collaboration.

In this article we provide a review of the VSD and focus on the important modifications and enhancements the project has undertaken since 2001.

THE VSD PROJECT SINCE 2001

Population

The VSD population has increased substantially since 2001, when 4 new MCOs joined the project to provide data on members younger than 18 years: Kaiser Permanente of Colorado (Denver, CO); Marshfield Clinic Research Foundation (Marshfield, WI); Health Partners Research Foundation (Minneapolis, MN); and Harvard Pilgrim/Harvard Vanguard (Boston, MA). In 2007, the VSD population expanded again as all participating sites except 2 began providing data on members of all ages. Currently, data for >18 million persons spanning 16 years are available for VSD research.

Data Sources, Collection, and Confidentiality

Since inception of the VSD, each MCO has prepared annual data files, called cycle files, that contain member information obtained from administrative files maintained by the individual MCOs. The cycle files include demographic and medical services information on their members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, mortality data, and additional birth information (eg, birth weight) when available. To ensure confidentiality and comply with federal regulations, each person within the VSD is assigned a unique, randomized VSD study identification number that is not linked to their MCO member identification number. VSD study identification numbers can be used to link data on demographics and medical services. A standardized data dictionary, which ensures data consistency across sites, is updated each year by the CDC and the VSD MCOs. Frequently, medical record data and, occasionally, participant survey or interview data are used to validate clinical diagnosis and vaccination data.

Distributed Data Model

From 1991 through 2000, the VSD used a centralized-data model, which required each MCO to send its cycle files to the CDC annually for merging and analyses. When data were needed for a specific VSD study, the CDC would send a subset of cycle data to the MCO responsible for performing the study analysis. Because of heightened confidentiality concerns, the centralized-data model was replaced by a more secure distributed-data model (DDM) in 2001 (see Fig 1).

FIGURE 1
FIGURE 1

Representation of the VSD DDM. Sites using the indirect method retrieve SAS programs at regular intervals from the hub. Output is then sent back to the hub where it is retrieved by analysts at the CDC. For sites that use the direct method, SAS programs and output are transferred through SAS Connect directly between the sites and the CDC. Both methods use encryption methods to secure data transfers.

The DDM allows each MCO to assemble and maintain its computerized data files on a secure server at the site rather than transferring data to the CDC,10 and ownership of the data is retained by the MCOs. Data required for specific VSD studies are transferred between the CDC and the VSD sites by using 2 secure methods known as the “indirect” and “direct” methods. With the indirect method, CDC and MCO computers share information through a secure server known as the “hub.” CDC researchers send computer programs to the hub, which are retrieved at specified intervals by an MCO computer. All computer programs are written for a statistical computer program (SAS [SAS Institute, Inc, Cary, NC]); data files are also stored by using this platform. Each MCO can retrieve and use its own SAS programs but cannot access programs or information that belongs to other MCOs. Each MCO sends its SAS logs, output, and analytical data subsets back to the hub for retrieval by CDC researchers. With the direct method, CDC researchers submit SAS programs interactively through a secure SAS remote session by using SAS Connect, an Internet communication protocol. Four SAS macros, which are a collection of SAS program statements that can be easily recalled, are used to facilitate access of the data and retrieval of SAS logs and output. All data transfers are conducted securely by using encrypted methods.

Dynamic Data Files

Development of the DDM as a secure data-transfer system enabled the VSD to restructure the way data files are collected and used, which led to the creation of dynamic data files (DDFs) in 2005. DDFs permit the ongoing capture of near real-time event-based MCO administrative data, including data on vaccination, hospitalizations, emergency department visits, clinical visits, MCO enrollment, and certain demographic characteristics. Most files are updated weekly with new data from each MCO, although some files are updated monthly or quarterly, depending on the capabilities of each site's data systems. Using the DDM, files are accessed by the CDC on an ongoing basis for analysis and/or extraction of necessary data for each ongoing study. The DDFs use the same standardized data dictionary as the cycle files and continue to provide the flexibility to conduct various types of studies. Additional tracking and data-quality measures were developed to monitor the new DDFs. The sample size of the DDF continuously increases as new data are added to the files, which date back to 1991. The combination of the DDM and DDFs enable the VSD to conduct near real-time postlicensure surveillance, enhance the timeliness of certain studies, and increase efficiency in the creation of cycle files.

Research and Surveillance Process

The VSD continues to conduct numerous studies on a wide range of immunization-safety topics. Table 1 lists the specific strategic priorities for the VSD. For each study, a team of VSD investigators, comprised of members from several of the participating MCOs and the CDC, develops a comprehensive study proposal that is presented and reviewed by the members of the project. This scientific proposal includes a detailed description of the hypothesis in question, study design, and analytical plan along with a rigorous review of the medical outcomes to be evaluated. All studies meet the necessary institutional review board and Health Insurance Portability and Accountability Act (HIPAA) requirements. Computerized data often supplemented with additional medical record or other data are used to create study-specific analytical data files that contain only an extremely small portion of the entire VSD data. Analyses and manuscript preparation are typically led by a single MCO or the CDC with input from participating investigators.

View this table:
TABLE 1

VSD Strategic Priorities

Study Designs

The VSD uses several analytical methodologies to evaluate vaccine safety. The calculation of background rates allows the VSD to conduct multiple types of observational studies and to calculate disease incidence and vaccination coverage. Early VSD studies typically used observational study designs such as retrospective cohort studies or case-control studies. Several recent VSD studies have used self-control case-series designs, which involve an analysis based on a person's exposure and control time windows, because appropriate independent control groups may be unavailable or subject to confounding.11,12 Because a large percentage of the VSD population is vaccinated, it is difficult to obtain data on unvaccinated persons to be used as a comparison or control group. Self-control case-series designs allow researchers to determine if the rate of AEFI is elevated in the hypothesized exposure window compared with the other time windows. Additional new case-only methods are being developed and refined to better control for seasonal differences in the uptake of vaccines relevant to studies that involve influenza vaccine and vaccines given seasonally in advance of school or college attendance.

Postmarketing Surveillance: Rapid Cycle Analysis

Since 2005, several new vaccines have been licensed: live, oral, human-bovine reassortant rotavirus vaccine (RotaTeq [Merck & Co, Inc, Whitehouse Station, NJ]), the tetravalent meningococcal polysaccharide-protein conjugate vaccine (Menactra [Sanofi Pasteur, Inc, Swiftwater, PA]), 2 tetanus, diphtheria, and acellular pertussis vaccines (Boostrix [GlaxoSmithKline Biologicals, Rixensart, Belgium] and Adacel [Sanofi Pasteur, Toronto, Ontario, Canada]), the human papillomavirus vaccine (Gardasil [Merck & Co, Inc), and a combination measles-mumps-rubella and varicella vaccine (ProQuad [Merck & Co, Inc]). Using DDFs, the VSD is conducting near real-time postmarketing surveillance for these 6 newly licensed vaccines. The studies, referred to as the rapid cycle analysis (RCA)13,14 projects, are an active surveillance system that routinely assesses possible associations between vaccines and predefined potential adverse events.

In the RCA, the observed number of suspected adverse events is compared with the expected number of events. The expected number of events may be determined from a variety of sources including previously determined background rates from the VSD or published literature, background rates from other data sources, concurrent comparison control groups, or self-control methods. Because the comparisons are conducted weekly, the estimates are adjusted by sequential methods to control for repeated analysis of the data.13,14 When conducting RCA, researchers are on alert for a “signal,” which is generated if the expected rate of adverse events is significantly greater than the control rate when adjusting for sequential methods and other factors. A VSD data-coordinating center was created to handle the increased demand for data management and analysis generated by these RCA studies.

Postmarketing Surveillance: VSD Collaboration With the VAERS

VSD data are also used in conjunction with information from VAERS to examine AEFI. VAERS is a passive surveillance system that receives adverse-event reports from various sources, including vaccine manufacturers, health care providers, immunization programs, and vaccine recipients.15 Possible associations are examined by comparing the number of adverse events reported to VAERS with background rates for these events from VSD data.16,–,18 Summaries of 2 such analyses for the newly licensed RotaTeq and Menactra vaccines are included in this article to illustrate this collaboration (see “Postmarketing Monitoring Supplementing VAERS Data With VSD Background Rates”).

Data-Sharing and Oversight

Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency. In 2002, the VSD established a data-sharing program that allows external researchers to analyze data sets from VSD studies published after August 2002 or to create novel analytical data sets for analysis by using VSD data through December 31, 2000. This program is administered through the National Center for Health Statistics of the CDC. More information on this program can be found at www.cdc.gov/vaccinesafety/Activities/VSD/Datasharing.html.

On 2 occasions, the VSD has invited external experts from a number of scientific disciplines and community members to contribute to the design, implementation, and presentation of high-priority studies. These studies include the study entitled “Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years” and the ongoing thimerosal and autism case-control study.19 A public-use data set from the thimerosal and neurodevelopmental outcomes study is available at www.cdc.gov/vaccinesafety/Concerns/Thimerosal/neuropsychological_Outcomes.html.

EXAMPLE STUDIES

The VSD conducts rigorous epidemiologic studies primarily on a wide range of vaccine-safety priorities as well as other immunization-related topics, including vaccine coverage, disease incidence, research methodology, cost-effectiveness, and medical informatics. Through its innovative approaches, the VSD has proven its ability to adapt and respond to the increasingly complex and controversial topics in immunization research. Below are a few examples that illustrate the capabilities of the VSD.

Hepatitis B Vaccine and Risk of Autoimmune Thyroid Disease20

A possible link between hepatitis B vaccine and autoimmune thyroid diseases such as Graves' disease and Hashimoto thyroiditis had been suggested by a study conducted in Europe and by reports to the VAERS. Supplementing patient interviews and medical record data with routinely collected automated data, the VSD was able to investigate this relationship through a multisite case-control study.20 Cases were initially identified through VSD cycle data and validated through medical record review, and then telephone interviews were conducted to verify hepatitis B vaccination status. The study analyzed 355 cases of Graves' disease, 418 cases of Hashimoto thyroiditis, and 1102 frequency-matched controls and revealed that having ever received hepatitis B vaccine did not increase the risk of either Graves' disease or Hashimoto thyroiditis.20 This study's results reveal the ability to collect comprehensive vaccine information and to accurately identify and confirm cases through alternative data-collection methods.

Safety of Trivalent Inactivated Influenza Vaccine in Children Aged 6 to 23 Months21

As a result of the decision by the CDC's Advisory Committee on Immunization Practices to recommend routine vaccination of all children aged 6 to 23 months with trivalent inactivated influenza vaccine (TIV) in 2004, the VSD proved to be well suited to assess the safety of TIV in this population. In one of the largest population-based TIV studies to date, the VSD conducted a retrospective cohort study of 45 356 children who received a total of 69 359 influenza vaccinations between January 1, 1991, and May 31, 2003.21 Self-control case-series methods were used for this analysis. Cycle files were analyzed to identify medically attended events seen in clinic, emergency department, or hospital settings after vaccination with TIV. Preliminary analyses revealed that gastritis/duodenitis was more likely to occur in the 14 days after TIV (matched odds ratios [ORs]: 5.50 [95% confidence interval (CI): 1.22–24.81] for control period 1 [0–3 days] and 4.33 [95% CI: 1.23–15.21] for control period 2 [1–14 days]). No other significant associations with medically attended events were found. Further analysis including chart review and a subanalysis of 28 820 children with no underlying medical conditions that would put them at increased risk of complications of influenza vaccination revealed that children vaccinated with TIV were not at increased risk of gastritis/duodenitis compared with the entire study population.21 This study supported the Advisory Committee on Immunization Practices vaccination recommendation by providing reassurance to support the safety of universally immunizing all children aged 6 to 23 months with influenza vaccination.

Early Thimerosal Exposure and Neuropsychological Outcomes at 7 to 10 Years19

In 1999, the Public Health Service and the American Academy of Pediatrics called on vaccine manufacturers to remove thimerosal, a mercury-containing preservative, from vaccines. The decision to remove thimerosal was a precautionary measure,22 and subsequent studies have found no significant association between thimerosal and neuropsychological deficits.19,23,–,31 In an effort to better improve on previous studies, the VSD was able to rigorously assess the relationship between thimerosal exposure and neuropsychological functioning through a retrospective cohort study with extensive assessments and interviews among the study population and their mothers. The study population included 1047 children between the ages of 7 and 10 years who were enrolled in 4 of the VSD MCOs and had received vaccinations as infants when thimerosal was used as a preservative in many childhood vaccines. For the analysis, the children were grouped according to their level of mercury exposure (low, medium, and high), which was determined from VSD MCO immunization records, medical records, personal immunization records, and parent interviews. Information on potential confounding factors was obtained from the interviews with mothers and from medical records. Standardized tests that assessed 42 neuropsychological outcomes, including speech and language measures, verbal memory, fine motor coordination, tics, and behavioral regulation, were administered to the children. Only 5% of the statistical tests (19 of 378) showed significant associations; 12 tests revealed a positive association, and 7 tests revealed a negative association. The vast majority of the tests revealed no association, and the 5% that showed associations could be explained by chance alone. The results added to accumulated evidence that thimerosal does not cause neuropsychological deficits in children.19 This study's results further show the ability of the VSD to supplement administrative data with data from other sources to conduct rigorous studies and test vaccine-safety hypotheses.

Postmarketing Monitoring Supplementing VAERS Data With VSD Background Rates

The VSD has collaborated with VAERS in conducting postmarketing surveillance of potential AEFI for newly licensed vaccines. The potential association between RotaTeq and intussusception was assessed by comparing the number of VAERS intussusception reports to the number of intussusception cases expected to occur by chance alone.16,32 To determine the expected number of cases that would occur by chance alone, the VSD first determined the background rates of natural intussusception (International Classification of Diseases, Ninth Revision code: 560.0) by using VSD data files from 2000 to 2004, when no rotavirus vaccine was in use. The analysis was stratified into 3 age groups, because background rates of natural intussusception and the number of doses administered varied substantially according to age. Using these data, the expected number of background cases was calculated by multiplying VSD background rates for each age group according to the estimated number of vaccine doses administered to that age group. The findings suggested that there is no association between RotaTeq vaccination and intussusception, because the number of cases of intussusception reported to the VAERS (32) was not elevated above the expected number of cases (52).16,32 Similar analyses were conducted to compare the potential association between Menactra and Guillain-Barré syndrome (GBS). For the study time period, the background incidence rate of GBS was determined to be 0.11 per 100 000 person-months in the VSD. By dividing the VAERS reporting rate of GBS (0.20 per 100 000 person-months) by the background incidence rate of GBS (0.11 per 100 000 person-months), the VSD determined the reporting rate ratio (RR) to be 1.77 (95% CI: 0.96–3.07).17,18 Although the data suggest a possible small increased risk of GBS in persons aged 11 to 19 who received Menactra vaccination, the findings should be viewed with caution.17,18

Postmarketing Monitoring Using VSD RCA

In addition to providing background rates to supplement the VAERS, the VSD is also conducting RCA studies to monitor the safety of several vaccines including RotaTeq, Menactra, Gardasil, Adacel and Boostrix, ProQuad, and seasonal influenza vaccination. Between May 2006 and May 2008, >205 000 doses of RotaTeq were administered orally to infants at ages 2, 4, and 6 months in VSD-monitored MCOs. Only 5 cases of intussusception within 30 days of vaccination were reported among RotaTeq recipients; in contrast, on the basis of historical background rates, 6.75 cases were expected to occur by chance alone. Only 2 of the intussusception cases were confirmed by medical chart review. This analysis suggested that there was no evidence that RotaTeq vaccine is associated with an increased risk for intussusception or other prespecified events.32,–,34 Between March 2005 and September 2008, >570 000 Menactra doses were delivered in participating MCOs, and no cases of GBS after medical record review were observed among vaccine recipients aged 11 to 19 years within 6 weeks of vaccination (0.9 cases would be expected during that period). During the same period, 5 unconfirmed cases of GBS were identified among an unvaccinated comparison group of >900 000 persons aged 11 to 19 years (Dr Lieu, update on Menactra RCA through September 2008, personal communication, October 20, 2008 and refs 14, 17, and 18). The results of neither study suggest an association of serious AEFI with these vaccines. In February 2008, VSD investigators presented the Advisory Committee on Immunization Practices with preliminary results from an analysis performed after a possible signal of seizure was observed in the VSD ProQuad RCA study.35 On the basis of >43 000 administered doses of the combination measles-mumps-rubella and varicella vaccine (MMRV), the attributable risk for seizures on days 7 to 10 after MMRV was calculated as 1 per 2000 doses compared with the measles-mumps-rubella and varicella vaccines administered separately but at the same visit.35 The VSD continues to investigate this association and continues to monitor the potential risk of GBS after Menactra. The VSD is now in the process of developing RCA studies for Kinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium), Pentacel (Sanofi Pasteur Ltd, Toronto, Canada), Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium), and pandemic H1N1 influenza vaccination.

POWER CONSIDERATIONS

With the addition of 4 new MCOS in 2001, the size of the VSD cohort increased and, with it, the statistical power available to detect rare vaccine-associated adverse events. Two examples, which illustrate the capacity of the VSD to detect rare events, follow.

The intussusception background rate of infants 6 to 35 weeks old, the age during which RotaTeq vaccine is given, is 32.4 per 100 000 person-years, as estimated from VSD data. The number of infants aged 6 to 35 weeks in the VSD cohort is ∼95 000. At 90% vaccination coverage and 80% power, it would require 4.3 years to detect an RR equivalent to 2.0, 1.4 years to detect an RR of 3.0, and 0.7 years to detect an RR of 4.0.

However, the VSD has limited capability to detect very rare AEFI in minimal time periods for minimal risk ratios. For example, the background rate of GBS among 11- to 19-year-olds is 1.3 to 1.4 per 100 000 person-years (unpublished data). The average monthly cohort of 11- to 19-year-olds in the VSD cohort is between 870 000 and 1 000 000 (average monthly 11- to 19-year-old cohort). At 70% vaccination coverage and 80% power, it would require ∼13 years to detect an RR of 2.0, 4 years to detect an RR of 3, and 2 years to detect an RR of 4.

CONCLUSIONS

The VSD has conducted important vaccine-safety research since its inception in 1990, and since 2001 it has made changes that have enhanced its ability to answer urgent questions about vaccine safety and other immunization-related issues and to inform US vaccination policy.

The ability of the VSD to adapt to a changing environment is exemplified by the development of the DDM, the creation of DDFs, and the implementation of RCA projects. The DDM, a system for securely and quickly transferring data within the VSD, was developed in response to heightened confidentiality concerns. The DDM enabled the development of the DDFs. Together, the DDM and DDFs enabled the implementation of RCA, which is allowing researchers to monitor events in near real-time after the introduction of new vaccines and new vaccine recommendations. The VSD continues to refine previously used methodologies and develop new methodologies, such as the maximized sequential probability ratio test (maxSPRT), which is applicable to the VSD's RCA.13,14,36 With the recent expansion of the VSD, the project is well positioned to conduct RCA studies and traditional VSD analyses on new vaccines being introduced for teenagers and young adults. Although the majority of VSD studies focus on hypotheses related to vaccine safety, the VSD has also demonstrated its ability to conduct studies on vaccine coverage,37,–,41 disease incidence,42,–,49 methodology,14,36,50 cost-effectiveness,51,–,53 and medical informatics.10,54

As described previously, the computerized vaccination records have been shown to be of high quality,55 whereas the accuracy of computerized records to determine medical outcomes varies.56 The VSD recognizes this limitation and uses additional data sources, especially medical chart review, to validate administrative data. Although not critical for the strategic priorities of the VSD (listed in Table 1), further studies that compare population characteristics and disease incidence rates to additional non-MCO sources characterizing the national population could be beneficial for VSD studies, especially those that describe estimates of vaccine coverage and disease incidence.

The VSD is one of several worldwide research programs that are able to conduct vaccine-safety studies by using large databases. Other established programs include the US Defense Medical Surveillance System,57,–,59 the UK General Practice Research Database,60 postlicensure epidemiology of childhood vaccinations in Denmark,61 and the Vietnam Vaccine Data Link.62 The VSD provides scientific expertise, continues to develop innovative approaches for vaccine safety, is the primary mechanism for population-based evaluations of vaccine safety in the United States, and may serve as a model for other patient-safety collaborative research projects.

Information about the VSD project can be obtained at www.cdc.gov/vaccinesafety/Activities/VSD.html.

ACKNOWLEDGMENTS

This study was supported, in part, by the VSD contract with America's Health Insurance Plans, funded by the CDC.

We thank all the organizations and their staff for participating in the VSD project, including the following key members: Rich Platt, MD, MS, Katherine Yih, PhD, Virginia Hinrichsen, MPH, Rich Fox, MPH, Renny Li, MS, RuiHua Yin, MS, Sharon Greene, PhD, and Irene Shui, MPH (Harvard Pilgrim/Harvard Vanguard), Leslie Kuckler and Amy Butani (Health Partners Research Foundation), Jim Donahue, PhD, DVM, Jeremy McCauley, MBA, and Stephanie Irving, MS (Marshfield Clinic Research Foundation), Christina Clarke, Matthew Daley, MD, Dave McClure, PhD, Jo Ann Shoup, MS, and Stan Xu, PhD (Kaiser Permanente of Colorado), Y. Craig Cheetham, PharmD, Wansu Chen, MS, Marlene Lugg, DrPH, Mike Marcy, MD, and Lina Sy, MPH (Kaiser Permanente of Southern California), Paula Ray, MPH (Kaiser Permanente of Northern California), Rachel Gold, PhD, MPH, John Mullooly, PhD, Lois Drew, BA, and Karen Riedlinger, MPH (Kaiser Permanente Northwest), Jennifer Nelson, PhD, Darren Malais, and Onchee Yu, MS (Group Health Cooperative), and Karen Broder, MD, MPH, Sophia Greer, MPH, Paul Gargiullo, PhD, John Iskander, MD, MPH, and William Thompson, PhD (CDC).

Footnotes

    • Accepted November 29, 2010.
  • Address correspondence to James Baggs, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd, Mail Stop D25, Atlanta, GA 30333. E-mail: jbaggs{at}cdc.gov

  • The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

  • FINANCIAL DISCLOSURE: Dr Baxter has received research grants from Sanofi Pasteur, MedImmune, Novartis, GlaxoSmithKline, Pfizer, and Merck; Dr Jackson has received research funding related to vaccines from the CDC, National Institutes of Health, Wyeth (Pfizer), Novartis, Sanofi Pasteur, and GlaxoSmithKline and has served as an advisory board member for Wyeth (Pfizer), Novartis, and GlaxoSmithKline; Dr Jacobsen has received grant funding from and served as an unpaid consultant to Merck Research Laboratories; Dr Klein has received research support from GlaxoSmithKline, Merck & Co, Sanofi Pasteur, Wyeth (Pfizer), Novartis, and MedImmune; and Mr Lewis in the past 3 years has worked on grants funded by Merck, Wyeth (Pfizer), Novartis, Sanofi Pasteur, GlaxoSmithKline, and MedImmune (now AstraZeneca). The other authors have indicated they have no financial relationships relevant to this article to disclose.

  • AEFI =
    adverse event(s) following immunization •
    CDC =
    Centers for Disease Control and Prevention •
    VSD =
    Vaccine Safety Datalink •
    MCO =
    managed care organization •
    VAERS =
    Vaccine Adverse Event Reporting System •
    DDM =
    distributed-data model •
    DDF =
    dynamic data file •
    RCA =
    rapid cycle analysis •
    TIV =
    trivalent inactivated influenza vaccine •
    OR =
    odds ratio •
    CI =
    confidence interval •
    GBS =
    Guillain-Barré syndrome •
    RR =
    rate ratio

REFERENCES

  1. 1.↵
    1. Roush SW,
    2. Murphy TV
    . Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. JAMA. 2007;298(18):2155–2163
    OpenUrlCrossRefPubMedWeb of Science
  2. 2.↵
    Centers for Disease Control and Prevention. Impact of vaccines universally recommended for children: United States, 1990–1998. MMWR Morb Mortal Wkly Rep. 1999;48(12):243–248
    OpenUrlPubMed
  3. 3.↵
    1. Chen RT,
    2. Mootrey G,
    3. DeStefano F
    . Safety of routine childhood vaccinations: an epidemiological review. Paediatr Drugs. 2000;2(4):273–290
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Bohlke K,
    2. Davis RL,
    3. Marcy SM,
    4. et al.
    ; Vaccine Safety Datalink Team. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics. 2003;112(4):815–820
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Cooper LZ,
    2. Larson HJ,
    3. Katz SL
    . Protecting public trust in immunization. Pediatrics. 2008;122(1):149–153
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Chen RT,
    2. DeStefano F,
    3. Davis RL,
    4. et al
    . The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA. Bull World Health Organ. 2000;78(2):186–194
    OpenUrlPubMedWeb of Science
  7. 7.↵
    1. DeStefano F
    . The Vaccine Safety Datalink project. Pharmacoepidemiol Drug Saf. 2001;10(5):403–406
    OpenUrlCrossRefPubMedWeb of Science
  8. 8.↵
    1. Chen RT,
    2. Glasser JW,
    3. Rhodes PH,
    4. et al
    . Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team. Pediatrics. 1997;99(6):765–773
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Wassilak SG,
    2. Glasser JW,
    3. Chen RT,
    4. Hadler SC
    . Utility of large-linked databases in vaccine safety, particularly in distinguishing independent and synergistic effects. The Vaccine Safety Datalink Investigators. Ann N Y Acad Sci. 1995;754:377–382
    OpenUrlCrossRefPubMedWeb of Science
  10. 10.↵
    1. Baggs J,
    2. Lewis E,
    3. Amundson JH,
    4. et al
    . Distributed data models for the Vaccine Safety Datalink (VSD). Presented at: 10th Annual HMO Research Network Conference. May 5, 2004; Dearborn, MI
  11. 11.↵
    1. Farrington CP,
    2. Nash J,
    3. Miller E
    . Case series analysis of adverse reactions to vaccines: a comparative evaluation. Am J Epidemiol. 1996;143(11):1165–1173
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Farrington CP
    . Control without separate controls: evaluation of vaccine safety using case-only methods. Vaccine. 2004;22(15–16):2064–2070
    OpenUrlCrossRefPubMedWeb of Science
  13. 13.↵
    1. Davis RL,
    2. Kolczak M,
    3. Lewis E,
    4. et al
    . Active surveillance of vaccine safety: a system to detect early signs of adverse events. Epidemiology. 2005;16(3):336–341
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Lieu TA,
    2. Kulldorff M,
    3. Davis RL,
    4. et al.
    ; Vaccine Safety Datalink Rapid Cycle Analysis Team. Real-time vaccine safety surveillance for the early detection of adverse events. Med Care. 2007;45(10 suppl 2):S89–S95
    OpenUrlCrossRefPubMedWeb of Science
  15. 15.↵
    1. Varricchio F,
    2. Iskander J,
    3. DeStefano F,
    4. et al
    . Understanding vaccine safety information from the Vaccine Adverse Event Reporting System. Pediatr Infect Dis J. 2004;23(4):287–294
    OpenUrlCrossRefPubMedWeb of Science
  16. 16.↵
    Centers for Disease Control and Prevention. Postmarketing monitoring of intussusception after RotaTeq vaccination: United States, February 1, 2006–February 15, 2007. MMWR Morb Mortal Wkly Rep. 2007;56(10):218–222
    OpenUrlPubMed
  17. 17.↵
    Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine—United States, June 2005–September 2006 [published correction appears in MMWR Morb Mortal Wkly Rep. 2006;55(43):1177]. MMWR Morb Mortal Wkly Rep. 2006;55(41):1120–1124
    OpenUrlPubMed
  18. 18.↵
    Centers for Disease Control and Prevention. Update: Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine—United States, October 2005–February 2006. MMWR Morb Mortal Wkly Rep. 2006;55(13):364–366
    OpenUrlPubMed
  19. 19.↵
    1. Thompson WW,
    2. Price C,
    3. Goodson B,
    4. et al.
    ; Vaccine Safety Datalink Team. Early thimerosal exposure and neuropsychological outcomes at 7 to 10 years. N Engl J Med. 2007;357(13):1281–1292
    OpenUrlCrossRefPubMedWeb of Science
  20. 20.↵
    1. Yu O,
    2. Bohlke K,
    3. Hanson CA,
    4. et al
    . Hepatitis B vaccine and risk of autoimmune thyroid disease: a Vaccine Safety Datalink study. Pharmacoepidemiol Drug Saf. 2007;16(7):736–745
    OpenUrlCrossRefPubMedWeb of Science
  21. 21.↵
    1. Hambidge SJ,
    2. Glanz JM,
    3. France EK,
    4. et al.
    ; Vaccine Safety Datalink Team. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. JAMA. 2006;296(16):1990–1997
    OpenUrlCrossRefPubMedWeb of Science
  22. 22.↵
    Centers for Disease Control and Prevention. Recommendations regarding the use of vaccines that contain thimerosal as a preservative. MMWR Morb Mortal Wkly Rep. 1999;48(43):996–998
    OpenUrlPubMed
  23. 23.↵
    1. Andrews N,
    2. Miller E,
    3. Grant A,
    4. Stowe J,
    5. Osborne V,
    6. Taylor B
    . Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004;114(3):584–591
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. DeStefano F
    . Vaccines and autism: evidence does not support a causal association. Clin Pharmacol Ther. 2007;82(6):756–759
    OpenUrlCrossRefPubMedWeb of Science
  25. 25.↵
    1. Heron J,
    2. Golding J
    ; ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004;114(3):577–583
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Madsen KM,
    2. Lauritsen MB,
    3. Pedersen CB,
    4. et al
    . Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics. 2003;112(3 pt 1):604–606
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Meadows M
    . IOM report: no link between vaccines and autism. FDA Consum. 2004;38(5):18–19
    OpenUrlPubMed
  28. 28.↵
    1. Parker SK,
    2. Schwartz B,
    3. Todd J,
    4. Pickering LK
    . Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data [published correction appears in Pediatrics. 2005;115(1):200]. Pediatrics. 2004;114(3):793–804
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Stehr-Green P,
    2. Tull P,
    3. Stellfeld M,
    4. Mortenson PB,
    5. Simpson D
    . Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med. 2003;25(2):101–106
    OpenUrlCrossRefPubMedWeb of Science
  30. 30.↵
    1. Taylor B
    . Vaccines and the changing epidemiology of autism. Child Care Health Dev. 2006;32(5):511–519
    OpenUrlCrossRefPubMedWeb of Science
  31. 31.↵
    1. Verstraeten T,
    2. Davis RL,
    3. DeStefano F,
    4. et al.
    ; Vaccine Safety Datalink Team. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases [published correction appears in Pediatrics. 2004;113(1):184]. Pediatrics. 2003;112(5):1039–1048
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Haber P,
    2. Patel M,
    3. Izurieta HS,
    4. et al
    . Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics. 2008;121(6):1206–1212
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Belongia E,
    2. Irving S,
    3. Shui I,
    4. et al
    . Rapid cycle analysis of pentavalent rotavirus (RotaTeq) vaccine safety in the Vaccine Safety Datalink population: preliminary results. Presented at: Advisory Committee on Immunization Practices meeting; June 25, 2008; Atlanta, GA
  34. 34.↵
    1. Irving SA,
    2. Belongia EA,
    3. Shui IM,
    4. et al
    . Rapid cycle analysis of pentavalent rotavirus vaccine safety in the Vaccine Safety Datalink Population. Presented at: the joint 46th Annual Infectious Diseases Society of America Conference and 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. October 25, 2008; Washington, DC
  35. 35.↵
    1. Klein N
    . Vaccine Safety Datalink project: evaluation of MMRV and febrile seizures. Presented at: Advisory Committee on Immunization Practices February 2008 meeting; February 27, 2008; Atlanta, GA
  36. 36.↵
    1. Glanz JM,
    2. McClure DL,
    3. Xu S,
    4. et al
    . Four different study designs to evaluate vaccine safety were equally validated with contrasting limitations. J Clin Epidemiol. 2006;59(8):808–818
    OpenUrlCrossRefPubMedWeb of Science
  37. 37.↵
    Centers for Disease Control and Prevention. Rapid assessment of influenza vaccination coverage among HMO members: northern California influenza seasons, 2001–02 through 2004–05. MMWR Morb Mortal Wkly Rep. 2005;54(27):676–678
    OpenUrlPubMed
  38. 38.↵
    1. Jackson LA,
    2. Neuzil KM,
    3. Baggs J,
    4. et al
    . Compliance with the recommendations for 2 doses of trivalent inactivated influenza vaccine in children less than 9 years of age receiving influenza vaccine for the first time: a Vaccine Safety Datalink study. Pediatrics. 2006;118(5):2032–2037
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    Centers for Disease Control and Prevention; Advisory Committee on Immunization Practices. Rotavirus vaccination coverage and adherence to the Advisory Committee on Immunization Practices (ACIP)-recommended vaccination schedule: United States, February 2006–May 2007. MMWR Morb Mortal Wkly Rep. 2008;57(15):398–401
    OpenUrlPubMed
  40. 40.↵
    1. Lin ND,
    2. Kleinman K,
    3. Chan KA,
    4. et al.
    ; Vaccine Safety Datalink Team. Variation in hepatitis B immunization coverage rates associated with provider practices after the temporary suspension of the birth dose. BMC Pediatr. 2006;6:31
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Lin ND,
    2. Kleinman K,
    3. Chan KA,
    4. et al.
    ; Vaccine Safety Datalink Group. Impact of the introduction of pneumococcal conjugate vaccine on immunization coverage among infants. BMC Pediatr. 2005;5:43
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Belay ED,
    2. Holman RC,
    3. Clarke MJ,
    4. et al
    . The incidence of Kawasaki syndrome in West Coast health maintenance organizations. Pediatr Infect Dis J. 2000;19(9):828–832
    OpenUrlCrossRefPubMedWeb of Science
  43. 43.↵
    1. Parashar UD,
    2. Holman RC,
    3. Bresee JS,
    4. et al
    . Epidemiology of diarrheal disease among children enrolled in four West Coast health maintenance organizations. Vaccine Safety Datalink Team. Pediatr Infect Dis J. 1998;17(7):605–611
    OpenUrlCrossRefPubMedWeb of Science
  44. 44.↵
    1. Averhoff F,
    2. Zucker J,
    3. Vellozzi C,
    4. et al
    . Adequacy of surveillance to detect endemic rubella transmission in the United States. Clin Infect Dis. 2006;43(suppl 3):S151–S157
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Mullooly JP,
    2. Bridges CB,
    3. Thompson WW,
    4. et al.
    ; Vaccine Safety Datalink Adult Working Group. Influenza- and RSV-associated hospitalizations among adults. Vaccine. 2007;25(5):846–855
    OpenUrlCrossRefPubMedWeb of Science
  46. 46.↵
    1. Bohlke K,
    2. Davis RL,
    3. DeStefano F,
    4. Marcy SM,
    5. Braun MM,
    6. Thompson RS
    . Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol. 2004;113(3):536–542
    OpenUrlCrossRefPubMedWeb of Science
  47. 47.↵
    1. Mullooly JP,
    2. Riedlinger K,
    3. Chun C,
    4. Weinmann S,
    5. Houston H
    . Incidence of herpes zoster, 1997–2002. Epidemiol Infect. 2005;133(2):245–253
    OpenUrlCrossRefPubMedWeb of Science
  48. 48.↵
    1. Izurieta HS,
    2. Thompson WW,
    3. Kramarz P,
    4. et al
    . Influenza and the rates of hospitalization for respiratory disease among infants and young children. N Engl J Med. 2000;342(4):232–239
    OpenUrlCrossRefPubMedWeb of Science
  49. 49.↵
    1. O'Brien MA,
    2. Uyeki TM,
    3. Shay DK,
    4. et al
    . Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics. 2004;113(3 pt 1):585–593
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. McClure DL,
    2. Glanz JM,
    3. Xu S,
    4. Hambidge SJ,
    5. Mullooly JP,
    6. Baggs J
    . Comparison of epidemiologic methods for active surveillance of vaccine safety. Vaccine. 2008;26(26):3341–3345
    OpenUrlCrossRefPubMedWeb of Science
  51. 51.↵
    1. Lieu TA,
    2. Black SB,
    3. Ray GT,
    4. Martin KE,
    5. Shinefield HR,
    6. Weniger BG
    . The hidden costs of infant vaccination. Vaccine. 2000;19(1):33–41
    OpenUrlCrossRefPubMedWeb of Science
  52. 52.↵
    1. Prosser LA,
    2. Bridges CB,
    3. Uyeki TM,
    4. et al
    . Values for preventing influenza-related morbidity and vaccine adverse events in children. Health Qual Life Outcomes. 2005;3:18
    OpenUrlCrossRefPubMed
  53. 53.↵
    1. Prosser LA,
    2. Bridges CB,
    3. Uyeki TM,
    4. et al
    . Health benefits, risks, and cost-effectiveness of influenza vaccination of children. Emerg Infect Dis. 2006;12(10):1548–1558
    OpenUrlPubMedWeb of Science
  54. 54.↵
    1. Hinrichsen VL,
    2. Kruskal B,
    3. O'Brien MA,
    4. Lieu TA,
    5. Platt R
    . Using electronic medical records to enhance detection and reporting of vaccine adverse events. J Am Med Inform Assoc. 2007;14(6):731–735
    OpenUrlCrossRefPubMedWeb of Science
  55. 55.↵
    1. Mullooly J,
    2. Drew L,
    3. DeStefano F,
    4. et al
    . Quality of HMO vaccination databases used to monitor childhood vaccine safety. Vaccine Safety Datalink Team. Am J Epidemiol. 1999;149(2):186–194
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Mullooly J,
    2. Drew L,
    3. DeStefano F,
    4. et al
    . Quality assessments of HMO diagnosis databases used to monitor childhood vaccine safety. Methods Inf Med. 2004;43(2):163–170
    OpenUrlPubMedWeb of Science
  57. 57.↵
    1. Davila JC,
    2. Payne DC,
    3. Zhang Y,
    4. et al
    . Quality assessment of nonanthrax vaccination data in the Defense Medical Surveillance System (DMSS), 1998–2004. Vaccine. 2008;26(12):1577–1584
    OpenUrlCrossRefPubMedWeb of Science
  58. 58.↵
    1. Payne DC,
    2. Rose CE Jr.,
    3. Aranas A,
    4. et al
    . Assessment of anthrax vaccination data in the Defense Medical Surveillance System, 1998–2004. Pharmacoepidemiol Drug Saf. 2007;16(6):605–611
    OpenUrlCrossRefPubMedWeb of Science
  59. 59.↵
    1. Rubertone MV,
    2. Brundage JF
    . The Defense Medical Surveillance System and the Department of Defense serum repository: glimpses of the future of public health surveillance. Am J Public Health. 2002;92(12):1900–1904
    OpenUrlCrossRefPubMedWeb of Science
  60. 60.↵
    1. Wong IC,
    2. Murray ML
    . The potential of UK clinical databases in enhancing paediatric medication research. Br J Clin Pharmacol. 2005;59(6):750–755
    OpenUrlCrossRefPubMedWeb of Science
  61. 61.↵
    1. Hviid A
    . Postlicensure epidemiology of childhood vaccination: the Danish experience. Expert Rev Vaccines. 2006;5(5):641–649
    OpenUrlCrossRefPubMedWeb of Science
  62. 62.↵
    1. Ali M,
    2. Canh GD,
    3. Clemens JD,
    4. et al.
    ; Vaccine Safety Datalink Group. The use of a computerized database to monitor vaccine safety in Viet Nam. Bull World Health Organ. 2005;83(8):604–610
    OpenUrlPubMedWeb of Science
View Abstract

 

View this article with LENS
Email

Alerts
Citation Tools
The Vaccine Safety Datalink: A Model for Monitoring Immunization Safety
James Baggs, Julianne Gee, Edwin Lewis, Gabrielle Fowler, Patti Benson, Tracy Lieu, Allison Naleway, Nicola P. Klein, Roger Baxter, Edward Belongia, Jason Glanz, Simon J. Hambidge, Steven J. Jacobsen, Lisa Jackson, Jim Nordin, Eric Weintraub
Pediatrics May 2011, 127 (Supplement 1) S45-S53; DOI: 10.1542/peds.2010-1722H
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Print
PDF
Insight Alerts

Subjects

Back to top