***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: PURPOSE Many challenges arise when conducting a sequentially monitored medical product safety surveillance evaluation using observational electronic data captured during routine care . We review existing sequential approaches for potential use in this setting , including a continuous sequential testing method that has been utilized within the Vaccine Safety Data link ( VSD ) and group sequential methods , which are used widely in r and omized clinical trials . METHODS Using both simulated data and preliminary data from an ongoing VSD evaluation , we discuss key sequential design considerations , including sample size and duration of surveillance , shape of the signaling threshold , and frequency of interim testing . RESULTS AND CONCLUSIONS All design s control the overall Type 1 error rate across all tests performed , but each yields different tradeoffs between the probability and timing of true and false positive signals . Design s tailored to monitor efficacy outcomes in clinical trials have been well studied , but less consideration has been given to optimizing design choices for observational safety setting s , where the hypotheses , population , prevalence and severity of the outcomes , implication s of signaling , and costs of false positive and negative findings are very different . Analytic challenges include confounding , missing and partially accrued data , high misclassification rates for outcomes presumptively defined using diagnostic codes , and unpredictable changes in dynamically accessed data over time ( e.g. , differential product uptake ) . Many of these factors influence the variability of the adverse events under evaluation and , in turn , the probability of committing a Type 1 error . Thus , to ensure proper Type 1 error control , planned sequential thresholds should be adjusted over time to account for these issues BACKGROUND To our knowledge , there are no published population -based studies on the safety of the inactivated trivalent influenza vaccine among children . OBJECTIVE To screen a large population of children for evidence of increased medical visits in the 2 weeks after  influenza vaccination  compared with 2 control periods . Secondary analyses included shorter risk periods and restricted age categories . DESIGN Self-control screening analysis . Children vaccinated from January 1 , 1993 , through December 31 , 1999 , were r and omly divided into 2 equal groups . In group 1 , risks of outpatient , emergency department , and inpatient visits during the 14 days after vaccination were compared with the risks of visits in 2 control periods . Significant plausible medically attended events identified in group 1 were then analyzed in group 2 , using the same 2 control periods . Medically attended events significant in both groups were considered potentially associated with vaccination and were assessed by medical record review . SETTING Five managed care organizations in the United States . PARTICIPANTS Children younger than 18 years who received an influenza vaccination in one of the managed care setting s ( N = 251 600 ) . MAIN OUTCOME MEASURE Among vaccinated children seen for a medically attended event , the odds of the visit occurring in the 2 weeks after vaccination vs during 1 of the 2 control periods . RESULTS Study participants incurred 1165 , 230 , and 489 different diagnoses during the 14 days after vaccination according to the outpatient , emergency department , and inpatient data , respectively . Four diagnoses were positively associated with the vaccine in both groups 1 and 2 : impetigo , dermatitis , uncomplicated diabetes mellitus , and ureteral disorder not otherwise specified . After medical record review , impetigo ( 9 cases ) in children 6 to 23 months old remained significantly associated with vaccination . CONCLUSION This large screening safety study did not reveal any evidence of important medically attended events associated with pediatric influenza vaccination The emergence of p and emic H1N1 influenza in 2009 has prompted public health responses , including production and licensure of new influenza A ( H1N1 ) 2009 monovalent vaccines . Safety monitoring is a critical component of vaccination programs . As proof-of-concept , the authors mimicked near real-time prospect i ve surveillance for prespecified neurologic and allergic adverse events among enrollees in 8 medical care organizations ( the Vaccine Safety Data link Project ) who received seasonal trivalent inactivated influenza vaccine during the 2005/06 - 2007/08 influenza seasons . In self-controlled case series analysis , the risk of adverse events in a prespecified exposure period following vaccination was compared with the risk in 1 control period for the same individual either before or after vaccination . In difference-in-difference analysis , the relative risk in exposed versus control periods each season was compared with the relative risk in previous seasons since 2000/01 . The authors used Poisson-based analysis to compare the risk of Guillain-Barré syndrome following vaccination in each season with that in previous seasons . Maximized sequential probability ratio tests were used to adjust for repeated analyses on weekly data . With administration of 1,195,552 doses to children under age 18 years and 4,773,956 doses to adults , no elevated risk of adverse events was identified . Near real-time surveillance for selected adverse events can be implemented prospect ively to rapidly assess seasonal and p and emic influenza vaccine safety BACKGROUND The combination DTaP-IPV/Hib vaccine was licensed in the United States in 2008 for children ages 6weeks through 4years with doses administered at 2 , 4 , 6 , and 15 - 18months of age . The aim of this study was to assess the safety of DTaP-IPV/Hib vaccine routinely administered as part of clinical care to infants at Kaiser Permanente Northern California . METHODS This was an observational , retrospective study that included all 2-month-old infants vaccinated with either DTaP-IPV/Hib or another DTaP-containing vaccine .  We monitored all subjects for non-elective hospitalizations , emergency department visits and selected outpatient outcomes ( seizures , Guillain-Barré Syndrome , encephalopathy , encephalitis , alteration of consciousness , meningitis , hypersensitivity reactions , immune thrombocytopenic purpura , hemolytic anemia , type 1 diabetes , and Kawasaki disease ) beginning with their first dose through 6months after a 4th dose or until 24months of age . We calculated incidence rate ratios ( IRRs ) in the primary analysis by comparing rates of outcomes during the post-vaccination risk interval with rates during a comparison interval more remote from vaccination . Secondary analyses compared outcomes after DTaP-IPV/Hib with those after other DTaP-containing vaccines . We review ed the medical records of selected outcomes . RESULTS From October 1 , 2008 through July 31 , 2010 , 14,042 subjects received a first dose of DTaP-IPV/Hib , 13,194 received 2 doses , 12,548 received 3 doses and 6702 received 4 doses . Overall , there were 166 comparisons with significantly elevated IRRs and 165 comparisons with significantly reduced IRRs . Medical record review of outcomes with significantly elevated IRRs in both the primary and secondary analyses did not suggest any relationship with DTaP-IPV/Hib . CONCLUSIONS This study did not detect any safety concerns following DTaP-IPV/Hib and provides reassurance that DTaP-IPV/Hib administered as part of routine care was not associated with unexpected safety risks . Clinical Trials.gov Identifier : NCT00804284 BACKGROUND The emergence of p and emic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated ( MIV ) and live , attenuated ( LAMV ) vaccines separate from seasonal trivalent inactivated ( TIV ) and live , attenuated ( LAIV ) influenza vaccines . A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination . PURPOSE To prospect ively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009 - 2010 season . METHODS The Vaccine Safety Data link ( VSD ) Project monitors ∼9.2 million members in eight U.S. medical care organizations . Electronic data on vaccines and pre-specified adverse events were up date d and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison . Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders . RESULTS As of May 1 , 2010 , a total of 1,345,663 MIV , 267,715 LAMV , 2,741,150 TIV , and 157,838 LAIV doses were administered in VSD . No significant associations were noted during sequential analyses for Guillain-Barré syndrome , most other neurologic outcomes , and allergic and cardiac events . For MIV , a statistical signal was observed for Bell 's palsy for adults aged ≥25 years on March 31 , 2010 , using the self-controlled approach . Subsequent analyses revealed no significant temporal cluster . Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bell 's palsy of 1.26 ( 95 % CI=0.97 , 1.63 ) . CONCLUSIONS No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009 - 2010 season in weekly sequential analyses . Seasonality likely contributed to the Bell 's palsy signal following MIV . Prospect i ve safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies BACKGROUND Live attenuated influenza vaccine ( LAIV ) was licensed in 2003 in the United States for use in individuals aged 5 - 49 years . METHODS A prospect i ve observational postmarketing study was conducted to evaluate the safety of LAIV .  Rates of medically attended events ( MAEs ) and serious adverse events ( SAEs ) in eligible children aged 5 - 17 years receiving LAIV as part of routine care from October 2003 to March 2008 were compared with rates in nonr and omized self , matched unvaccinated , and matched trivalent inactivated influenza vaccine (TIV)-vaccinated controls . All MAEs and SAEs through 42 days postvaccination and all hospitalizations and deaths through 6 months postvaccination were analyzed . Statistical significance was assigned without multiplicity adjustment . RESULTS 43,702 LAIV recipients were matched with similar numbers of TIV-vaccinated and unvaccinated children . Of approximately 9500 MAE incidence rate comparisons , 204 were statistically significantly higher and 168 were statistically significantly lower in LAIV recipients versus controls . No pattern of MAE rate differences suggested a safety signal with LAIV .  Asthma/wheezing MAEs were not statistically increased in LAIV recipients . No anaphylaxis events occurred within 3 days postvaccination . Rates of SAEs were similar between LAIV and control groups . Two SAEs were considered possibly related to LAIV :  Bell 's palsy and nonspecific paroxysmal spell . CONCLUSIONS Results of this postlicensure evaluation of LAIV safety in US children aged 5 - 17 years are consistent with preapproval clinical studies and Vaccine Adverse Event Reporting System reports , both of which demonstrated no significant increase in asthma/wheezing events or other adverse outcomes among eligible children who received LAIV BACKGROUND A combined measles , mumps , rubella , varicella live vaccine ( MMRV , Merck and Co. , Inc. , US ) was recently licensed in the US . Pre-licensure clinical trial data showed a significant increase in fever in days 5 - 12 following MMRV vaccination as compared to the vaccines given separately ( MMR+V ) . This post-licensure retrospective cohort study was undertaken to assess the incidence of febrile convulsion following MMRV . METHODS Children ages 12 - 60 months who received a first dose of MMRV in February 2006-June 2007 in a managed care organization were included in the study . Subjects were optimally matched on age , sex , and calendar date of vaccination to children who received MMR+V concomitantly in November 2003-January 2006 , before MMRV licensure . Potential cases of febrile convulsion were identified through administrative data and adjudicated by expert panel , according to pre-specified criteria . RESULTS During the 30 days post-vaccination , there were 128 and 94 potential convulsion cases among the 31,298 children in the MMRV and MMR+V cohorts , respectively . After review of available medical charts and adjudication , there were 84 cases of confirmed febrile convulsion , 44 ( 1.41/1000 ) and 40 ( 1.28/1000 ) in the MMRV and MMR+V cohorts , respectively ( RR=1.10 , 95 % CI=0.72 , 1.69 ) . In days 5 - 12 following vaccination , a pre-specified period of interest , the respective numbers were 22 ( 0.70/1000 ) and 10 ( 0.32/1000 ) ( RR=2.20 , 95 % CI=1.04 , 4.65 ) . CONCLUSION These data suggest that the risk of febrile convulsion is increased in days  
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Partially elapsed risk window and data accrual lags were the most cited barriers to monitor AEFIs in near real-time .
Conclusion Routinely collected electronic healthcare data are increasingly used to detect AEFI signals in near real-time .