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3 Existing Data Sources and Systems While the Advisory Committee on Immunization Practices (ACIP) is tasked with making recommendations on vaccine usage, the National Vac- cine Advisory Committee (NVAC) directs research priorities on vaccine development, efficacy, and safety. Included in the membership of NVAC are a number of ex officio representatives from federal agencies engaged in vaccine safety monitoring. Several systems that are part of the federal re- search infrastructure provide postmarketing data on vaccines that are used for immunization safety surveillance, to determine immunization coverage, and to assess the effects of vaccines on vaccine-preventable diseases. In turn, vaccine safety research is often conducted using data obtained from ongoing surveillance. This chapter reviews these systems and discusses how data from these systems are used to help assess the safety of cumulative immunizations, the timing of immunizations, and other aspects of the im- munization schedule. IMMUNIZATION SAFETY SURVEILLANCE A number of systems for ongoing monitoring and study of the safety of vaccines recommended for use are in place in the United States (and other nations as well), where the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and vaccine manufac- turers have systems in place for postmarketing surveillance and research. CDC and FDA manage a number of postmarketing activities, includ- ing surveillance of vaccine-preventable diseases, monitoring of adverse events following immunization, tracking of vaccine coverage and issuance 39

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40 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY of guidance on vaccine shortages. Although vaccine safety is rigorously as- sessed during prelicensing clinical trials, this postmarketing monitoring is important because the sample sizes in prelicensing clinical trials may not have been adequate to detect rare adverse events, the prelicensing study population may not have been monitored for long-term adverse events, and populations may not have been heterogeneous (Baggs et al., 2011; Chen et al., 2000). Consequently, postmarketing evaluation of vaccine safety is needed to assess rare, delayed, or unusual reactions and in general provides a fuller understanding of the safety of vaccines recommended in the immu- nization schedule (Chen et al., 1997). Ongoing surveillance systems serve as the primary resource for infor- mation and research on postmarketing vaccine safety. The CDC Immuniza- tion Safety Office (ISO) maintains three major postmarketing surveillance systems: the Vaccine Adverse Event Reporting System (VAERS; jointly managed with FDA), the Vaccine Safety Datalink (VSD), and the Clinical Immunization Safety Assessment (CISA) Network. Most CDC immuniza- tion activities are located in the National Center for Immunization and Respiratory Diseases. Since 2005, the ISO was moved to the National Cen- ter for Emerging and Zoonotic Infectious Diseases as its mission is clearly distinct from other immunization programs within the agency. This organi- zational change ensures the separation at CDC between vaccine promotion and safety. In addition to the surveillance systems managed by CDC, FDA has established a supplementary mechanism for monitoring vaccine safety called the Sentinel Initiative. Vaccine Adverse Event Reporting System VAERS is a passive reporting surveillance system that is jointly man- aged by CDC and FDA and serves as a warning system for potential adverse events and side effects from a recommended vaccine that may not have been detectable in clinical trials (NVAC, 2011). Anyone, including parents and providers, may submit voluntary, spontaneous reports of adverse events ob- served after administration of licensed vaccines. Reports received by VAERS are analyzed and recorded for possible follow-up (CDC and FDA, 2012). Although VAERS is useful for the early detection of signals of adverse events, the data obtained from the system have limitations. The reports re- ceived may not be fully documented, or the adverse event attributed to the vaccine may, in actuality, be a case not caused by the vaccine on the basis of background rates of clinical events. In addition, data on the number of doses of vaccine administered or number of vaccinated people do not exist and are thus not available for use as the denominator, so researchers can- not calculate what proportion of individuals were affected by an adverse event for comparison with the background rate of the event in the general

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EXISTING DATA SOURCES AND SYSTEMS 41 population. Because no denominator data are available, VAERS cannot be used to evaluate causality. The VAERS data are useful, however, for the de- velopment of adverse event signals and the formation of related hypotheses that can be further tested and validated by more robust methods. Vaccine Safety Datalink One system better suited to the testing of hypotheses about vaccine safety is VSD. The VSD project was formed in the 1990s as a collaborative effort between CDC and a group of managed care organizations (MCOs) to maintain a large linked database for monitoring immunization safety and studying potential rare and serious adverse events. The number of VSD member sites has increased over the years and now includes nine MCOs that enroll approximately 9.5 million children and adults, or about 3 percent of the U.S. population. VSD sites are located at geographically diverse locations in California, Colorado, Georgia, Hawaii, Massachusetts, Michigan, Minnesota, Oregon, and Washington (Frank DeStefano, CDC, personal communication, October 18, 2012). Because the data in the data- base are generated as a by-product of the routine administration of health care and the system does not rely on voluntary adverse event reporting (as VAERS does), the problems of underreporting and recall bias are reduced. VSD is a useful system that includes demographic data and informa- tion on the medical services that have been provided to those enrolled in the health plans, such as age and gender; vaccinations; hospitalizations; outpatient clinic, emergency department, and urgent care visits; mortality data; and additional birth information (e.g., birth weight) (Baggs et al., 2011). Automated pharmacy and laboratory data as well as information on diagnostic procedures (e.g., radiography and electroencephalography) that the patient has undergone are also included (Chen et al., 2000). Data on adverse events, including deaths (from probabilistic matching of death files), are routinely collected (Chen et al., 1997). Covariates used to control for potential confounders include birth certificates and variables from the decennial census at the zip code level, in addition to demographic data from the health plans. Each site collects data on vaccinations (the type, date, and concurrent vaccinations), medical outcomes (diagnoses and procedures associated with outpatient, inpatient, and urgent care visits), and birth and census data. To ensure compliance of federal regulations and to protect confidentiality, each person within the VSD is assigned a unique random VSD study iden- tification number which is not linked to their MCO member identification number. These VSD study identification numbers can be used to link data on demographics and medical services (Baggs et al., 2011). Since 2001, VSD has used a distributed data model whereby each MCO

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42 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY assembles and maintains its computerized files on a secure server at the site. This distributed data model has permitted the creation of dynamic data files that permit the ongoing capture of near real-time event-based MCO administrative data. These include data on vaccinations, hospitalizations, emergency department and clinical care visits, and certain demographic characteristics. While most files are updated weekly with new data from each MCO, some files are updated less frequently (Baggs et al., 2011). This organization of the data enables near real-time postmarketing surveillance to be conducted and enhances the timeliness of certain studies. Surveillance and Research The VSD has been used to conduct rigorous epidemiological studies on a wide range of immunization safety topics. Strategic priorities for research and surveillance are developed and updated regularly. The following priori- ties were reported in 2011 (Baggs et al., 2011): • Evaluate the safety of newly licensed vaccines. • Evaluate the safety of new immunization recommendations for existing vaccines. • Evaluate clinical disorders after immunization. • Assess vaccine safety in particular populations at high risk. • Develop and evaluate methodologies for vaccine safety assessment. The enhancements in data transfer and updating permit near real-time postmarketing surveillance. Adverse events identified in the VSD system are analyzed by use of an active surveillance system called Rapid Cycle Analysis. Every week, the Rapid Cycle Analysis team determines the rates of adverse events associated with newly licensed or recommended vaccines in the study population. This information allows VSD researchers to compare the rates of adverse events in similar groups of people to determine if an event is related to the vaccine. If an increased risk is detected, VSD project scientists implement a formal, population-based epidemiological study to test the hypothesis of a causal relationship. VSD data are also used in conjunction with data from VAERS to de- termine, for example, whether the number of adverse events reported to VAERS exceeds the background occurrence of the events shown in VSD. VSD has been used to conduct rigorous studies on a wide range of top- ics on vaccine safety, as well as studies on immunization coverage, disease incidence, research methodologies, cost-effectiveness, and medical infor- matics (Baggs et al., 2011; DeStefano, 2001). For example, VSD has been used to study immunization safety concerns, such as the risk of seizures following receipt of the whole-cell pertussis vaccine or the measles, mumps,

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EXISTING DATA SOURCES AND SYSTEMS 43 rubella (MMR) vaccine, and to evaluate the safety of thimerosal-containing vaccines (Barlow et al., 2001; CDC, 2011b; Verstraeten et al., 2003). Importantly, in selected studies, the automatically collected adminis- trative data in VSD have been supplemented with information from other sources to test selected hypotheses on vaccine safety. For example, in a study examining the hepatitis B vaccine and the risk of autoimmune thy- roid disease, cases were initially identified through VSD and then validated through a review of the medical records. Telephone interviews were then conducted with the parents to confirm the child’s hepatitis B vaccination status (Yu et al., 2007). As another example, in a study of early thimerosal exposure and neu- ropsychological outcomes, mercury exposure was determined from VSD medical and personal immunization records and interviews with parents. The study also used the results of standardized tests that assessed 42 neu- ropsychological outcomes (Thompson et al., 2007). Studying the Safety of the Immunization Schedule Some characteristics of VSD lend themselves to the study of the safety of the immunization schedule. The fact that MCOs have different vaccina- tion policies (after the first year of life)—along with deviations in the immu- nization schedule due to variations in clinical practice, vaccine shortages, problems with access, or intentional denial of vaccine coverage—yields dif- ferences in vaccine exposure in this large cohort (Chen et al., 1997). These differences have been leveraged to examine the safety of aspects of the immunization schedule (Chen et al., 1997; see Appendix D). Because rela- tively few children are completely unvaccinated, study designs do not rely on comparison groups of children but instead use case-only methods such as self-controlled case-series designs (Baggs et al., 2011; see Appendix D). Limitations of VSD The MCOs that make up VSD are largely private plans; thus, the popu- lation, although large, is not demographically representative of the children in the United States. Safety outcomes or other medical consequences may not vary on the basis of income or insurance status; but other information collected by VSD—such as the completeness of the immunization schedule, immunization delays, or the amount of time that an individual receives immunizations off of the immunization schedule—may be related to such socioeconomic factors (Luman et al., 2005). Furthermore, because beneficiaries move between plans because of choice, a job change, or other factors, the ability to monitor children for an extended period may be limited. Although the average time spent in

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44 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY the VSD is not known, more than half of the children born in 2001 and included in the system at that time are still in the system (Frank DeStefano, personal communication). Although studies have used the VSD to select the cohort and have augmented VSD data with data from other sources, the committee was not aware of any studies that have monitored a VSD cohort outside the health plan structure over time. This sort of longer-term follow-up may be important to the study of the safety of the immunization schedule, and if such follow-up is undertaken, ethical and confidentiality issues will need to be explored. Sentinel Initiative The Sentinel Initiative program, established by FDA, is designed to build and implement a national electronic system to monitor the safety of FDA-approved drugs and other medical products. The pilot project for this initiative, the Mini-Sentinel, is currently collecting data from 17 col- laborating institutions with databases containing health care data collected from 2000 to 2011 from 126 million participants and data on more than 345 million person-years of observation time (Mini-Sentinel Coordinating Center, 2011). The Mini-Sentinel is an active surveillance system that uses a distrib- uted database design, which means that the data remain in their existing secure environments at collaborating institutions rather than being central- ized into one database. When it is fully implemented, the Sentinel Initiative will complement the existing passive surveillance system, VAERS, in captur- ing reports of adverse events after immunization and will enable FDA to use existing electronic health care data to perform near real-time analyses (NVAC, 2011). FDA’s Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program similarly captures claims data from the Mini-Sentinel sites to es- tablish a large cohort with which to analyze vaccine exposure and adverse events with a high degree of statistical power. This active surveillance system, which is updated quarterly, has the capacity to link claims data from collaborating health insurers to immunization registries. To date, the program has been used to conduct various epidemiological analyses, such as an investigation of postmarketing adverse events after administration of the 2009 pandemic H1N1 influenza vaccine which evaluated vaccine safety data for over 38 million individuals (Nguyen et al., 2012; see Appendix D). Although PRISM’s database is larger than that of the VSD, PRISM is newer and less able to rapidly conduct medical record review to confirm suspected outcomes of interest initially identified in claims data. Though neither Mini- Sentinel nor any of the other existing surveillance systems described above have yet been used to evaluate health outcomes associated with the entire

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EXISTING DATA SOURCES AND SYSTEMS 45 recommended childhood immunization schedule, there is great potential in these large database initiatives to monitor rare adverse events potentially associated with the childhood immunization schedule. Clinical Immunization Safety Assessment Network CDC also maintains the CISA Network to perform clinical research on biological mechanisms of adverse events, which are often hypothesized on the basis of reports to VAERS. The CISA Network is a network of six U.S. academic medical centers with experts in vaccinology and vaccine safety who collaborate in discussions about adverse events (CDC, 2011c). Although VSD researchers conduct population-based research on vaccine safety, experts in the CISA Network investigate the pathophysiological basis for an adverse event to counsel clinicians on individual variations in reactions to vaccines and to help policy makers determine precaution and contraindication criteria for vaccines. CISA investigators have performed causality assessments on reports received from VAERS, including a recent assessment of serious neurologic adverse events following immunization with the H1N1 influenza vaccine (Williams et al., 2011). The CISA Net- work has maintained for future study a repository of biological samples obtained from individuals who have experienced unusual adverse events (NVAC, 2011). National Institutes of Health The National Institutes of Health (NIH) have an important role in maintaining the safety of vaccines, from basic biological study that leads to new vaccine development through supporting research to address ongoing vaccine safety and efficacy. Two recent initiatives from the NIH are par- ticularly relevant to the study of the recommended childhood immunization schedule. Several NIH institutes, including the National Institute of Allergy and Infectious Diseases (NIAID) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, have collaborated with the CDC to announce a funding opportunity entitled Research to Advance Vaccine Safety. Researchers from eligible institutions are invited to propose research on topics including but not limited to “evaluation of existing child- hood immunization schedules to optimize safe and long-term protective immune memory” (Curlin et al., 2011, p. S13) and “comparison of the immunologic and physiologic effects of different combinations of vaccines and different schedules” (Curlin et al., 2011, p. S14). In addition, research topics can include studies that seek to determine genetic susceptibility to serious adverse events following vaccination and research that attempts

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46 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY to identify the molecular basis for differential immune responses to vaccina- tion when an underlying health condition is present (Curlin et al., 2011). Similarly, the Human Immunology Project Consortium (HIPC) pro- gram was developed by the NIAID in 2010 to further an understanding of the human immune system and its regulation. HIPC researchers are using innovative technologies to profile human responses and provide new biolog- ical evidence to help determine if there is a relationship between short-term adverse events following vaccination and long-term health issues (HIPC, 2012). Although the HIPC offers a promising approach to studying health outcomes of the childhood immunization schedule, researchers will require data on the effects of age, environment, infectious exposures, lifestyle, and many other possibly confounding variables before any conclusions can be drawn (Hackett, 2012). Thus, it is critical to continue epidemiological study of vaccines through systems like VAERS, VSD, and the Sentinel Initiative, as well as study of biological mechanisms through CISA and NIH. DATABASES USED TO ASSESS COVERAGE Data from another set of databases are used to assess immunization coverage, including the population-based National Immunization Survey (NIS) telephone survey and the state-level immunization registries. National Immunization Survey The surveillance systems described above are tools to monitor vaccine safety. Ensuring that vaccines are safe and present minimal health risks to individuals is an important part of keeping the majority of the population immunized and preserving community immunity. Furthermore, because no vaccine alone is 100 percent effective at preventing disease for any in- dividual, sustaining a low incidence of vaccine-preventable diseases in the United States requires a population-based effort. As such, it is important to have tools to examine populations that may not be adequately immunized and to monitor trends in vaccine coverage. The National Center for Im- munization and Respiratory Diseases and the National Center for Health Statistics jointly operate the NIS for this purpose. The NIS is a large random-digit-dialing telephone survey that collects data on immunization coverage for U.S. children aged 19 to 35 months. The survey sampling methodology provides both national and state-level estimates of coverage. State-level estimates can be used to compare immu- nization rates among states; the national estimates can be used to compare rates by race/ethnicity or other subpopulation. The survey is conducted in two parts: a telephone interview is conducted with the parents or caregiv- ers in the household, and if the parents or caregivers consent, a subsequent

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EXISTING DATA SOURCES AND SYSTEMS 47 survey is mailed to the child’s immunization provider to verify the parental report of immunizations. Providers are asked to fill out a list of all im- munizations, the dates when they were given to the child, and whether the immunizations were given in that or another medical practice. In addition to immunization history, providers are asked about other characteristics of the practice, such as the type of facility, the number of physicians working at the practice, vaccine ordering, and whether the practice reported any of the child’s immunizations to the community or state registry (CDC, 2011a). Using this method, the NIS obtains data for more than 17,000 U.S. children in all 50 states and selected territories and urban areas. The com- bined surveys produce coverage data for children in the United States by individual vaccine, as well as immunization schedule completion indicators, such as completion of the 4:3:1:3:3:1:4 seven-vaccine series (four or more doses of diphtheria-tetanus-pertussis vaccine, three or more doses of polio- virus vaccine, one or more doses of MMR vaccine, three or more doses of Haemophilus influenzae type b, vaccine, three or more doses of hepatitis B vaccine, one or more doses of varicella vaccine, and four doses of seven- valent pneumococcal conjugate vaccine [PCV]). In addition to immuniza- tion information, the surveys also obtain information for other variables, such as poverty status; provider facility; race and ethnicity; participation in programs such as Vaccines for Children or the Women, Infants, and Children food program; and a history of breast-feeding. Scientists often use data from the NIS to track trends in immunization coverage over time and to compare groups of children by demographic characteristics and immunization coverage to formulate hypotheses about what factors may be causing significant differences in immunization cover- age (CDC, 2011a). State Immunization Registries CDC supports a network of immunization information systems (IISs), formerly called immunization registries, which consist of computerized, population-based databases that confidentially collect and consolidate im- munization records from partnering vaccine providers. The 50 states, the District of Columbia, and 5 cities receive CDC grants to maintain their IISs. Providers are able to use the IISs to determine appropriate patient vaccinations, manage their vaccine inventories, and generate reminder and recall messages. The percentage of children whose immunization records are entered into an IIS varies widely by grantee: in 2010, the Connecticut Immunization Registry and Tracking System reported that 75 percent of eligible children in Connecticut participated, whereas Maryland’s IIS par- ticipation rate was only 42 percent (CDC, 2012a). The IISs count children as participants only if they have received at least two immunizations from

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48 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY a reporting vaccination provider, and reporting requirements vary between grantees (CDC, 2012c; Hedden et al., 2012). IISs are primarily useful for tracking vaccine coverage, and those with a high participation rate and comprehensive data are potentially well-suited to evaluate postmarketing vaccine effectiveness (Cortese et al., 2011; Guh and Hadler, 2011). However, as electronic health records become more widely available in the United States, the opportunities for linking immu- nization history with other health data may increase. IISs offer some benefits over systems in private health care plans, such as the VSD, for measuring immunization coverage. The systems are estab- lished in more than 50 geographic locations and receive data from a larger variety of immunization providers, including providers in private and pub- lic health care systems. In 2010, 11,536 public and 36,512 private provid- ers reported participation in the IISs (CDC, 2012c). Nevertheless, children receive immunizations in a number of settings that may not report to an IIS. The utility of immunization registries is likely to increase, as the provi- sions of the American Reinvestment and Recovery Act for the meaning- ful use of interoperable electronic health records require the linkage of a region’s IIS to an electronic health record to qualify for incentives (CDC, 2012b). DATABASES EXAMINING ADVERSE EVENTS AFTER IMMUNIZATION FOR VACCINE-PREVENTABLE DISEASES A set of national and state databases with data on hospital discharges can be used to monitor events requiring medical attention that occur after immunization with selected vaccines. Data from state-level claims databases and surveys assessing the characteristics of office visits can be used in the same way. If adverse events have a specific diagnosis code, these can be monitored as well. One such family of health care databases is the Agency for Healthcare Research and Quality–sponsored Healthcare Cost and Utilization Project (HCUP). Through a partnership between industry and government at the state and federal levels, HCUP has the largest collection of longitudinal data on hospital care in the United States, with these data dating back to 1988. All data collected in HCUP are obtained at the encounter level from patients of all payment types (all payers), including uninsured individuals. Some of the HCUP databases most relevant to the examination of immu- nization outcomes include the following (AHRQ, 2009): • The Nationwide Inpatient Sample, which collects inpatient data from more than 1,000 hospitals in the United States, is the largest database of its kind in the United States.

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EXISTING DATA SOURCES AND SYSTEMS 49 • The Kids’ Inpatient Database (KID), which also collects hospital in- patient data for children and adolescents ages 20 years and younger, is the only all-payer database with this kind of information. • The Nationwide Emergency Department Sample captures the re- cords for emergency department encounters from approximately 1,000 community hospitals. Because the HCUP family of databases includes all discharges at the state level and a large sample at the national level, data from those data- bases can be used to detect rare events, such as adverse reactions. These data have been used, for example, to examine intussusception rates before and after the introduction of rotavirus vaccination to determine whether in- creases occurred (Simonsen et al., 2001; Tate et al., 2008; Yen et al., 2011). These analyses generally use data from the universal state-level inpatient da- tabases of several states. Analyses like these require specific diagnosis codes for the adverse events and, in addition, require a causal chain that links the adverse event to vaccines. This is the case for rotavirus and intussusception but is less frequent for adverse events with other vaccines. In addition, data from these databases can be used to assess the burden of disease for a variety of vaccine-preventable diseases. For example, Ma et al. (2009) used data from KID to assess the burden of hospitalizations for rotavirus infections in children receiving Medicaid compared with that in children not receiving Medicaid. Fischer et al. (2007) used data from these databases to establish the rate of hospitalizations associated with diarrhea and rotavirus infection before the introduction of a new rotavirus vaccine, including baseline rates, trends, and risk factors. Finally, because they are longitudinal, data from the databases can be used to track the effects of the introduction of a vaccine on the incidence of the disease that it is intended to prevent. For example, these databases have been used to show the reduction in hospitalizations for pneumococ- cal pneumonia, all-cause pneumonia, and pneumococcal meningitis after introduction of PCV7 for all children and for children with sickle cell disease (Grijalva et al., 2007; McCavit et al., 2012; Simonsen et al., 2011; Tsai et al., 2008). Databases have been used in the same manner to show reductions in the numbers of hospitalizations for acute gastroenteritis after introduction of a rotavirus vaccine (Curns et al., 2010). A similar database (the National Hospital Discharge Survey, sponsored by the National Center for Health Statistics) has been used, in combina- tion with estimates of vaccine effectiveness, to predict the reduction of the disease burden after introduction of a vaccine against that disease (Curns et al., 2009). Among the limitations of studies like these are that they generally do not rely on laboratory-confirmed disease, and because they are observational, researchers are not able to control the exposures in the

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50 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY population, and thus may not be able to clearly identify if the disease is a direct result of the vaccine. State-Level Medicaid Claims and Related Local Databases Data from state-level Medicaid and health plan databases have been used to assess the disease burden overall and in specific regions or for spe- cific payers (Poehling et al., 2003). Data from these local claims databases have also been used to examine reductions in the incidence of disease after introduction of a vaccine, for example, the reduction in the incidence of otitis media after the introduction of PCV7 (Poehling et al., 2003, 2007). Furthermore, data from these state-level Medicaid or plan-level claims data- bases have also been used to assess the effectiveness of local immunization campaigns as seen from reductions in the incidence of disease. For example, data from local claims databases in Tennessee were used to assess the ef- fectiveness of school-based influenza campaigns (Grijalva et al., 2010a,b). National Ambulatory Care Databases CDC sponsors both the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey. The National Am- bulatory Medical Care Survey is a national survey of visits to nonfederal office-based physicians who are primarily engaged in direct patient care; the National Hospital Ambulatory Care Survey is a national survey of visits to emergency department doctors and the outpatient departments of general and short-stay hospitals. Both surveys collect data on the use and provision of ambulatory medical care services. Physicians also provide information about themselves and their practices. Data from these databases have been used to examine the effect of vaccine introduction on ambulatory care visits of a given type, such as examination of reductions in the rates of visits for otitis media after the introduction of PCV7 mentioned earlier (Grijalva et al., 2006). IMMUNIZATION DATA SYSTEMS IN OTHER COUNTRIES A number of other countries have in place data systems that are suc- cessfully used to investigate vaccine safety and coverage. Although these systems and those in place in the United States have key differences, start- ing with differences in the recommended immunization schedules, other countries may be well-equipped to provide data on safety concerns with the immunization schedule identified by the committee. Descriptions of immu- nization data systems from three countries, including Canada, with popu- lations similar to the population in the United States are presented below.

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EXISTING DATA SOURCES AND SYSTEMS 51 United Kingdom Residents of the United Kingdom (England, Northern Ireland, Scotland, and Wales) access health care through the taxpayer-funded National Health Service (NHS), which issues to each resident a unique identifying NHS number. Residents receive immunizations from their general practitioners, who serve as the initial point of access for all primary care provided by the NHS. General practitioners also issue referrals for elective or acute second- ary care, although patients can seek care at a hospital emergency room at any time. Like many other countries, including the United States, the United Kingdom (UK) has a spontaneous reporting system that passively collects data on suspected adverse events after the receipt of vaccines and other drugs. This system is known as the “Yellow Card scheme,” so named because yellow cards were historically used for reporting in the British National Formulary. The Yellow Card passive surveillance system was in- troduced in 1965 and is currently operated by the pharmaceutical licensing authority in the United Kingdom, the Medicines and Healthcare Products Regulatory Agency. Today, UK health care professionals and patients can also report potential adverse events electronically or by phone. In addition, vaccine manufacturers have more recently been required to conduct post- marketing pharmacovigilance for adverse events after immunization or to undertake special studies when appropriate. The Medicines and Healthcare Products Regulatory Agency also co- sponsors the United Kingdom’s Clinical Practice Research Datalink (CPRD) with the NHS National Institute for Health Research. The CPRD was in- troduced in March 2012 and contains observational data that build on the data collected for its predecessor, the General Practice Research Database (GPRD). The GPRD is a primary care database that contains anonymous records on consultations, secondary care referrals, prescriptions, and vac- cinations for about 5 percent of the population of the United Kingdom. The CPRD aims to maximize the linkages that can be made between the data that the GPRD collects and the data from other disease registries or from health care databases maintained in the United Kingdom (CPRD, 2012). The Health Protection Agency (HPA) is an independent body in the United Kingdom with functions analogous to those of CDC in the United States. Among the HPA’s responsibilities are a number of vaccine safety activities, including performing clinical trials, surveillance for vaccine- preventable diseases, and mathematical modeling and economic analyses; maintaining adequate vaccine coverage; and monitoring the safety and ef- ficacy of the vaccines provided by the NHS. The HPA conducts analytical studies on adverse event signals that arise from the Yellow Card system. HPA researchers also often use the GPRD to

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52 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY investigate health concerns, but the study population is not large enough to examine the rare adverse events associated with vaccines (Miller, 2012). The Hospital Episode Statistics (HES) database contains records for all hospital admissions in the United Kingdom, along with the individual’s NHS number for each admission. Using the NHS number, researchers can contact an individual’s general practitioner to obtain immunization records and link those data to any hospital admission from the HES. England and Wales maintain national child health databases that rou- tinely collect immunization records and can likewise be linked with the HES by use of an NHS number and specified approvals. This method has been used to investigate adverse event signals, such as a suspected increased risk of purpura or convulsions from the meningococcal group C conjugate vaccine and a potential association between MMR and idiopathic throm- bocytopenic purpura (Andrews et al., 2007; Miller et al., 2001). Denmark Denmark is uniquely positioned to build and maintain large cohorts for the evaluation of vaccine safety thanks to the Danish Civil Registration System (CRS) and the national health care system. The CRS was established in 1968 and registered every living person in Denmark at that time. Every living resident in Denmark, including noncitizens, is issued a unique per- sonal identification number, and the CRS collects data on each individual’s gender, date of birth, place of birth, place of residence, citizenship status, and parents and spouses, and the CRS continuously updates vital statistics (Pedersen et al., 2006). Linking a personal identification number to the data collected by the CRS makes it possible to track demographic trends and vital statistics for Danish residents over time. This identifier is also used to link individuals with data collected by Denmark’s many health care registries. The National Board on Health administers registries on the incidence of specific diseases (e.g., the National Diabetes Register and the Danish Cancer Register), and since 1990, Denmark has maintained a registry containing information on all vaccinations administered to children aged 18 years and younger. General practitioners report incidences of vaccination to a state-based administrative registry and are in turn reimbursed by the national health insurance system (Thygesen et al., 2011). Epidemiological research on vaccine safety is conducted with data from these registries by the Department of Epidemiology Research at the Statens Serum Institut, one of Denmark’s largest health research institu- tions (Statens Serum Institut, 2012). Because each health-related registry records the resident’s CRS, it is possible to link the data collected by sepa- rate registries. Therefore, much of the formative research on vaccine safety

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EXISTING DATA SOURCES AND SYSTEMS 53 has been conducted in Denmark with registry linkages. These linkages of data between the childhood vaccination registry and other disease-specific registries provide data that can be used to evaluate hypotheses on vaccine safety for large cohorts of Danish residents (often, more than 500,000). For example, the cohort study design has been used to investigate associations between MMR and autism, childhood vaccinations and type 1 diabetes, and thimerosal-containing vaccines and autism (Hviid et al., 2003, 2004; Madsen et al., 2002). Canada Canada’s health care system has some similarities with those in coun- tries such as Denmark and the United Kingdom, including the provision of primary care health services without cost sharing. Unlike those countries, Canada’s health care system is provincial, rather than federal, meaning that coverage varies across the 13 separate provinces. The determination of an immunization schedule is no exception: each province is given authority to create its own immunization schedule, although evidence of vaccine safety and efficacy is still reviewed by the National Advisory Committee on Immunization. Nevertheless, provinces may have very similar schedules for one vaccine; for example, the only province that does not recommend immunization with MMR at 12 months of age is Prince Edward Island, which recommends the vaccine’s first administration 3 months later at age 15 months. For another vaccine, that for hepatitis B, the differences are more striking: the province of Prince Edward Island recommends admin- istration of the first dose in infancy, whereas its provincial neighbor, Nova Scotia, does not recommend administration of the first dose until grade 8 (Macdonald and Bortolussi, 2011). Canada also has a spontaneous reporting system for suspected adverse events related to vaccines, the Vaccine Associated Adverse Event Report- ing System, which was established in 1987. Today, the passive surveillance system is called the Canadian Adverse Events Following Immunization Surveillance System and is maintained by the Public Health Agency of Canada. Health care professionals in Canada can submit reports of sus- pected adverse events to their local public health authority. Unlike in the United States, however, Canada has no system for the general public to report events without a health professional, who must submit the required form. In the provinces of Manitoba, New Brunswick, Nova Scotia, Ontario, Quebec, and Saskatchewan, reporting of adverse events after immunization is required by law (Public Health Agency of Canada, 2006). To supplement its passive surveillance system, Canada implemented the Immunization Monitoring Program, Active (IMPACT) in 1991. The IMPACT network is based in 12 pediatric hospitals and is maintained by

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54 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY the Canadian Paediatric Society. In IMPACT, a nurse monitor and clinical investigator regularly review admission records at network hospitals. Any suspected adverse events are reported to the vaccinee’s local public health authorities and the Public Health Agency of Canada (Public Health Agency of Canada, 2006). IMPACT data have been used in studies of suspected adverse events after immunization, including studies of the risk of seizures or encephalopathy after implementation of acellular pertussis-containing vaccines (Scheifele et al., 2003). International Collaborations In addition to country-specific data systems, some international col- laborations seek to improve assessments of vaccine safety. The Brighton Collaboration is a global research network comprising more than 300 vaccine safety experts from 124 countries, including the United States. The focus of their work is to enhance vaccine safety and it falls into five categories: capacity building, clinical assessments, communication, data linkages, and research standards. Included in their activities is an effort to standardize case definitions of adverse events after immunization (Brighton Collaboration, 2012). In addition, the Brighton Collaboration operates the Vaccine Adverse Event Surveillance and Communication Network of data linkages in Eu- rope, which is funded by the European Centre for Disease Prevention and Control (VAESCO, 2010). To date, this network of investigative centers has conducted a five-country distributed case-control study to evaluate the risk of Guillain-Barré syndrome after administration of the pandemic influenza (H1N1) vaccine and the incidence of idiopathic thrombocytopenic purpura after immunization with MMR in a combined sample from Denmark and the United Kingdom (Dieleman et al., 2011; Madsen et al., 2002). REFERENCES AHRQ (Agency for Healthcare Research and Quality). 2009. Overview of HCUP. Rock- ville, MD: Agency for Healthcare Research and Quality. http://www.hcup-us.ahrq.gov/ overview.jsp (accessed September 19, 2012). Andrews, N., J. Stowe, E. Miller, and B. Taylor. 2007. Post-licensure safety of the meningococ- cal group C conjugate vaccine. Human Vaccines 3(2):59-63. Baggs, J., J. Gee, E. Lewis, G. Fowler, P. Benson, T. Lieu, A. Naleway, N.P. Klein, R. Baxter, E. Belongia, J. Glanz, S.J. Hambidge, S.J. Jacobsen, L. Jackson, J. Nordin, and E. Weintraub. 2011. The Vaccine Safety Datalink: A model for monitoring immunization safety. Pediatrics 127(Suppl 1):S45-S53.

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EXISTING DATA SOURCES AND SYSTEMS 55 Barlow, W.E., R.L. Davis, J.W. Glasser, P.H. Rhodes, R.S. Thompson, J.P. Mullooly, S.B. Black, H.R. Shinefield, J.I. Ward, S.M. Marcy, F. DeStefano, R.T. Chen, V. Immanuel, J.A. Pearson, C.M. Vadheim, V. Rebolledo, D. Christakis, P.J. Benson, N. Lewis, and Centers for Disease Control and Prevention Vaccine Safety Datalink Working Group. 2001. The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vac- cine. New England Journal of Medicine 345(9):656-661. Brighton Collaboration. 2012. Brighton Collaboration. Brighton, United Kingdom: Brighton Collaboration. https://brightoncollaboration.org/public.html (accessed August 5, 2012). CDC (Centers for Disease Control and Prevention). 2011a. National Immunization Survey. Atlanta, GA: Centers for Disease Control and Prevention. http://www.cdc.gov/nchs/nis. htm (accessed June 15, 2012). CDC. 2011b. Vaccine Safety Datalink (VSD) project. Atlanta, GA: Centers for Disease Con- trol and Prevention. http://www.cdc.gov/vaccinesafety/Activities/VSD.html (accessed June 12, 2012). CDC. 2011c. Clinical Immunization Safety Assessment (CISA) network. Atlanta, GA: Centers for Disease Control and Prevention. http://www.cdc.gov/vaccinesafety/Activities/cisa.html (accessed November 28, 2012). CDC. 2012a. 2010 IISAR data participation rates. Atlanta, GA: Centers for Disease Control and Prevention. http://www.cdc.gov/vaccines/programs/iis/annual-report-IISAR/2010- data.html#child (accessed September 3, 2012). CDC. 2012b. Meaningful use. Atlanta, GA: Centers for Disease Control and Prevention. http:// www.cdc.gov/ehrmeaningfuluse (accessed October 3, 2012). CDC. 2012c. Progress in immunization information systems—United States, 2010. MMWR Morbidity and Mortality Weekly Reports 61(25):464-467. CDC and FDA (Food and Drug Administration). 2012. Vaccine Adverse Event Reporting System. Atlanta, GA: Centers for Disease Control and Prevention; Rockville, MD: Food and Drug Administration. http://vaers.hhs.gov/index (accessed June 1, 2012). Chen, R.T., J.W. Glasser, P.H. Rhodes, R.L. Davis, W.E. Barlow, R.S. Thompson, J.P. Mullooly, S.B. Black, H.R. Shinefield, and C.M. Vadheim. 1997. Vaccine Safety Datalink project: A new tool for improving vaccine safety monitoring in the United States. Pediatrics 99(6):765-773. Chen, R., F. DeStefano, R. Davis, L. Jackson, R. Thompson, J. Mullooly, S. Black, H. Shinefield, C. Vadheim, and J. Ward. 2000. The Vaccine Safety Datalink: Immunization research in health maintenance organizations in the USA. Bulletin of the World Health Organization 78(2):186-194. Cortese, M.M., J. LeBlanc, K.E. White, R.C. Jerris, P. Stinchfield, K.L. Preston, J. Meek, L. Odofin, S. Khizer, C.A. Miller, V. Buttery, S. Mijatovic-Rustempasic, J. Lewis, U.D. P ­ arashar, and L.C. Immergluck. 2011. Leveraging state immunization information sys- tems to measure the effectiveness of rotavirus vaccine. Pediatrics 128(6):E1474-E1481. CPRD (Clincal Practice Research Datalink). 2012. Clinical Practice Research Datalink (CPRD). London, United Kingdom: Medicines and Healthcare Products Regulatory Agency, National Institute for Health Research. http://www.cprd.com/intro.asp (accessed July 2, 2012). Curlin, G., S. Landry, J. Bernstein, R.L. Gorman, B. Mulach, C.J. Hackett, S. Foster, S.E. Miers, and P. Strickler-Dinglasan. 2011. Integrating safety and efficacy evaluation throughout vaccine research and development. Pediatrics 127(Suppl 1):S9-S15. Curns, A.T., F. Coffin, J.W. Glasser, R.I. Glass, and U.D. Parashar. 2009. Projected impact of the new rotavirus vaccination program on hospitalizations for gastroenteritis and rotavi- rus disease among US children <5 years of age during 2006-2015. Journal of Infectious Diseases 200(Suppl 1):S49-S56.

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56 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Curns, A.T., C.A. Steiner, M. Barrett, K. Hunter, E. Wilson, and U.D. Parashar. 2010. Re- duction in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: Analysis of hospital discharge data from 18 US states. Journal of Infectious Diseases 201(11):1617-1624. DeStefano, F. 2001. The Vaccine Safety Datalink project. Pharmacoepidemiology and Drug Safety 10(5):403-406. Dieleman, J., S. Romio, K. Johansen, D. Weibel, J. Bonhoeffer, and M. Sturkenboom. 2011. Guillain-Barré syndrome and adjuvanted pandemic influenza A (H1N1) 2009 vaccine: Multinational case-control study in Europe. BMJ 343:d3908. Fischer, T.K., C. Viboud, U. Parashar, M. Malek, C. Steiner, R. Glass, and L. Simonsen. 2007. Hospitalizations and deaths from diarrhea and rotavirus among children <5 years of age in the United States, 1993-2003. Journal of Infectious Diseases 195(8):1117-1125. Grijalva, C.G., K.A. Poehling, J.P. Nuorti, Y. Zhu, S.W. Martin, K.M. Edwards, and M.R. Griffin. 2006. National impact of universal childhood immunization with pneumococ- cal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics 118(3):865-873. Grijalva, C.G., J.P. Nuorti, P.G. Arbogast, S.W. Martin, K.M. Edwards, and M.R. Griffin. 2007. Decline in pneumonia admissions after routine childhood immunisation with pneumococ- cal conjugate vaccine in the USA: A time-series analysis. Lancet 369(9568):1179-1186. Grijalva, C.G., Y. Zhu, L. Simonsen, and M.R. Griffin. 2010a. Establishing the baseline bur- den of influenza in preparation for the evaluation of a countywide school-based influenza vaccination campaign. Vaccine 29(1):123-129. Grijalva, C.G., Y. Zhu, L. Simonsen, E. Mitchel, and M.R. Griffin. 2010b. The population impact of a large school-based influenza vaccination campaign. PLoS One 5(11):e15097. Guh, A.Y., and J.L. Hadler. 2011. Use of the state immunization information system to assess rotavirus vaccine effectiveness in Connecticut, 2006–2008. Vaccine 29(37):6155-6158. Hackett, C. 2012. Phenotyping of Human Immune Responses in Vaccination. Presentation to Meeting 1 of the Institute of Medicine Committee on the Assessment of Studies of Health Outcomes Related to the Recommended Childhood Immunization Schedule, Washington, DC, February 9. Hedden, E.M., A.B. Jessop, and R.I. Field. 2012. Childhood immunization reporting laws in the United States: Current status. Vaccine 30(49):7059-7066. HIPC (Human Immunology Project Consortium). 2012. The Human Immunology Project Consortium. Rockville, MD: Human Immunology Project Consortium, Division of Al- lergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases. http://www.immuneprofiling.org/hipc/page/show (accessed October 1, 2012). Hviid, A., M. Stellfeld, J. Wohlfahrt, and M. Melbye. 2003. Association between thimerosal- containing vaccine and autism. Journal of the American Medical Association 290(13): 1763-1766. Hviid, A., M. Stellfeld, J. Wohlfart, and M. Melbye. 2004. Childhood vaccination and type 1 diabetes. New England Journal of Medicine 350(14):1398-1404. Luman, E.T., L.E. Barker, K.M. Shaw, M.M. McCauley, J.W. Buehler, and L.K. Pickering. 2005. Timeliness of childhood vaccinations in the United States: Days undervacci- nated and number of vaccines delayed. Journal of the American Medical Association 293(10):1204-1211. Ma, L., A.C. El Khoury, and R.F. Itzler. 2009. The burden of rotavirus hospitalizations among Medicaid and non-Medicaid children younger than 5 years old. American Journal of Public Health 99(Suppl 2):S398-S404. Macdonald, N., and R. Bortolussi. 2011. A harmonized immunization schedule for Canada: A call to action. Paediatrics and Child Health 16(1):29-31.

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EXISTING DATA SOURCES AND SYSTEMS 57 Madsen, K.M., A. Hviid, M. Vestergaard, D. Schendel, J. Wohlfahrt, P. Thorsen, J. Olsen, and M. Melbye. 2002. A population-based study of measles, mumps, and rubella vaccination and autism. Ugeskrift for Laeger 164(49):5741-5744. McCavit, T.L., L. Xuan, S. Zhang, G. Flores, and C.T. Quinn. 2012. Hospitalization for inva- sive pneumococcal disease in a national sample of children with sickle cell disease before and after PCV7 licensure. Pediatric Blood and Cancer 58(6):945-949. Miller, E. 2012. Vaccine policy and safety surveillance in England and Wales. Presentation to Meeting 3 of the Institute of Medicine Committee on the Assessment of Studies of Health Outcomes Related to the Recommended Childhood Immunization Schedule, Washington, DC, May 29. Miller, E., P. Waight, C.P. Farrington, N. Andrews, J. Stowe, and B. Taylor. 2001. Idio- pathic thrombocytopenic purpura and MMR vaccine. Archives of Disease in Childhood 84(3):227-229. Mini-Sentinel Coordinating Center. 2011. Mini-Sentinel distributed database “at a glance.” Sil- ver Spring, MD: Food and Drug Administration, Sentinel Initiative. http://mini-sentinel. org/about_us/MSDD_At-a-Glance.aspx (accessed November 12, 2012). Nguyen, M., R. Ball, K. Midthun, and T.A. Lieu. 2012. The Food and Drug Administration’s Post-licensure Rapid Immunization Safety Monitoring program: Strengthening the fed- eral vaccine safety enterprise. Pharmacoepidemiol Drug Safety 21(Suppl 1):S291-S297. NVAC (National Vaccine Advisory Committee). 2011. National Vaccine Advisory Commit- tee draft white paper on the United States vaccine safety system. Unpublished. National Vaccine Advisory Committee, Washington, DC. Pedersen, C.B., H. Gøtzsche, J.Ø. Møller, and P.B. Mortensen. 2006. The Danish Civil Regis- tration System. Danish Medical Bulletin 53(4):441-449. Poehling, K.A., P.G. Szilagyi, K. Edwards, E. Mitchel, R. Barth, H. Hughes, B. Lafleur, S.J. Schaffer, B. Schwartz, and M.R. Griffin. 2003. Streptococcus pneumoniae-related ill- nesses in young children: Secular trends and regional variation. Pediatric Infectious Disease Journal 22(5):413-418. Poehling, K.A., P.G. Szilagyi, C.G. Grijalva, S.W. Martin, B. LaFleur, E. Mitchel, R.D. Barth, J.P. Nuorti, and M.R. Griffin. 2007. Reduction of frequent otitis media and pressure- equalizing tube insertions in children after introduction of pneumococcal conjugate vac- cine. Pediatrics 119(4):707-715. Public Health Agency of Canada. 2006. Canadian immunization guide. Ottawa, Ontario, Canada: Public Health Agency of Canada. Scheifele, D.W., S.A. Halperin, and CPS/Health Canada, Immunization Monitoring Program, Active (IMPACT). 2003. Immunization Monitoring Program, Active: A model of active surveillance of vaccine safety. Seminars in Pediatric Infectious Diseases 14(3):213-219. Simonsen, L., D. Morens, A. Elixhauser, M. Gerber, M. Van Raden, and W. Blackwelder. 2001. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception. Lancet 358(9289):1224-1229. Simonsen, L., R.J. Taylor, Y. Young-Xu, M. Haber, L. May, and K.P. Klugman. 2011. Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitaliza- tion and mortality in all age groups in the United States. mBio 2(1):1-10. Statens Serum Institut. 2012. Statens Serum Institut. Copenhagen, Denmark: Statens Serum Institut. http://www.ssi.dk/English.aspx (accessed July 10, 2012). Tate, J.E., L. Simonsen, C. Viboud, C. Steiner, M.M. Patel, A.T. Curns, and U.D. Parashar. 2008. Trends in intussusception hospitalizations among US infants, 1993-2004: Impli- cations for monitoring the safety of the new rotavirus vaccination program. Pediatrics 121(5):e1125-e1132.

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58 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY Thompson, W.W., C. Price, B. Goodson, D.K. Shay, P. Benson, V.L. Hinrichsen, E. Lewis, E. Eriksen, P. Ray, and S.M. Marcy. 2007. Early thimerosal exposure and neuropsychologi- cal outcomes at 7 to 10 years. New England Journal of Medicine 357(13):1281-1292. Thygesen, L.C., C. Daasnes, I. Thaulow, and H. Brønnum-Hansen. 2011. Introduction to Danish (nationwide) registers on health and social issues: Structure, access, legislation, and archiving. Scandinavian Journal of Public Health 39(Suppl 7):S12-S16. Tsai, C.J., M.R. Griffin, J.P. Nuorti, and C.G. Grijalva. 2008. Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine in the United States. Clinical Infectious Diseases 46(11):1664-1672. VAESCO (Vaccine Adverse Event Surveillance and Communication). 2010. Vaccine Adverse Event Surveillance and Communication (VAESCO). Stockholm, Sweden: Vaccine Ad- verse Event Surveillance and Communication. http://vaesco.net/vaesco.html (accessed August 5, 2012). Verstraeten, T., R.L. Davis, F. DeStefano, T.A. Lieu, P.H. Rhodes, S.B. Black, H. Shinefield, R.T. Chen, and Vaccine Safety Datalink Team. 2003. Safety of thimerosal-containing vac- cines: A two-phased study of computerized health maintenance organization databases. Pediatrics 112(5):1039-1048. Williams, S.E., B.A. Pahud, C. Vellozzi, P.D. Donofrio, C.L. Dekker, N. Halsey, N.P. Klein, R.P. Baxter, C.D. Marchant, P.S. Larussa, E.D. Barnett, J.I. Tokars, B.E. McGeeney, R.C. Sparks, L.L. Aukes, K. Jakob, S. Coronel, J.J. Sejvar, B.A. Slade, and K.M. Edwards. 2011. Causality assessment of serious neurologic adverse events following 2009 H1N1 vaccination. Vaccine 29(46):8302-8308. Yen, C., J.E. Tate, J.D. Wenk, J.M. Harris II, and U.D. Parashar. 2011. Diarrhea-associated hospitalizations among US children over 2 rotavirus seasons after vaccine introduction. Pediatrics 127(1):e9-e15. Yu, O., K. Bohlke, C.A. Hanson, K. Delaney, T.G. Rees, A. Zavitkovsky, P. Ray, J. Mullooly, S.B. Black, and P. Benson. 2007. Hepatitis B vaccine and risk of autoimmune thy- roid disease: A Vaccine Safety Datalink study. Pharmacoepidemiology and Drug Safety 16(7):736-745.