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1.  Simulation Study of the Effect of Influenza and Influenza Vaccination on Risk of Acquiring Guillain-Barré Syndrome 
Emerging Infectious Diseases  2015;21(2):224-231.
Under typical conditions, such as influenza incidence rates of >5% and vaccine effectiveness >60%, vaccination reduced risk.
It is unclear whether seasonal influenza vaccination results in a net increase or decrease in the risk for Guillain-Barré syndrome (GBS). To assess the effect of seasonal influenza vaccination on the absolute risk of acquiring GBS, we used simulation models and published estimates of age- and sex-specific risks for GBS, influenza incidence, and vaccine effectiveness. For a hypothetical 45-year-old woman and 75-year-old man, excess GBS risk for influenza vaccination versus no vaccination was −0.36/1 million vaccinations (95% credible interval −1.22 to 0.28) and −0.42/1 million vaccinations (95% credible interval, –3.68 to 2.44), respectively. These numbers represent a small absolute reduction in GBS risk with vaccination. Under typical conditions (e.g. influenza incidence rates >5% and vaccine effectiveness >60%), vaccination reduced GBS risk. These findings should strengthen confidence in the safety of influenza vaccine and allow health professionals to better put GBS risk in context when discussing influenza vaccination with patients.
doi:10.3201/eid2102.131879
PMCID: PMC4313628  PMID: 25625590
seasonal influenza; influenza vaccination; Guillain-Barré syndrome; risk modeling; decision tree modeling; viruses; vaccination; influenza; modeling
2.  Quality of Life and Associated Socio-Clinical Factors after Encephalitis in Children and Adults in England: A Population-Based, Prospective Cohort Study 
PLoS ONE  2014;9(7):e103496.
Objective
We sought to measure HRQoL in all-cause encephalitis survivors and assess the impact of various socio-clinical factors on outcome.
Methods
We used a prospective cohort study design, using the short-form 36 (SF-36) to measure the HRQoL in patients 15 years and older, and the short-form 10 (SF-10) for patients less than 15 years old. We posted questionnaires to individuals six months after discharge from hospital. All scores were normalised to the age- and sex-matched general population. We used multivariate statistical analysis to assess the relative association of clinical and socio-demographic variables on HRQoL in adults.
Results
Of 109 individuals followed-up, we received 61 SF-36 and twenty SF-10 questionnaires (response rate 74%). Patients scored consistently worse than the general population in all domains of the SF-36 and SF-10, although there was variation in individual scores. Infectious encephalitis was associated with the worst HRQoL in those aged 15 years and over, scoring on average 5.64 points less than immune-mediated encephalitis (95% CI −8.77– −2.89). In those aged less than 15 years the worst quality of life followed encephalitis of unknown cause. Immuno compromise, unemployment, and the 35–44 age group all had an independent negative association with HRQoL. A poor Glasgow Outcome Score was most strongly associated with a poor HRQoL. Less than half of those who had made a ‘good’ recovery on the score reported a HRQoL equivalent to the general population.
Conclusions
Encephalitis has adverse effects on the majority of survivors’ wellbeing and quality of life. Many of these adverse consequences could be minimised by prompt identification and treatment, and with better rehabilitation and support for survivors.
doi:10.1371/journal.pone.0103496
PMCID: PMC4114751  PMID: 25072738
3.  Oral Fluid Testing for Pertussis, England and Wales, June 2007–August 2009  
Emerging Infectious Diseases  2014;20(6):968-975.
Existing pertussis surveillance systems tend to underidentify less severe cases among older children and adults. For routine follow-up of notified, nonconfirmed, clinically diagnosed pertussis cases, use of an oral fluid test was pilot tested in England and Wales during June 2007–August 2009. During that period, 1,852 cases of pertussis were confirmed by established laboratory methods and another 591 by oral fluid testing only. Although introduction of serologic testing in 2002 led to the greatest increase in ascertainment of pertussis, oral fluid testing increased laboratory ascertainment by 32% overall; maximal increase (124%) occurred among children 5–9 years of age. Patients whose pertussis was confirmed by oral fluid testing were least likely to be hospitalized, suggesting that milder community cases were being confirmed by this method. Oral fluid testing is an easily administered, noninvasive surveillance tool that could further our understanding of pertussis epidemiology and thereby contribute to decisions on vaccination strategies.
doi:10.3201/eid2006.131069
PMCID: PMC4036755  PMID: 24856627
4.  Ethnic disparities in acquiring 2009 pandemic H1N1 influenza: a case–control study 
BMC Public Health  2014;14:214.
Background
Novel risk factors were associated with the 2009 pandemic A/H1N1 virus (pH1N1). Ethnicity was among these risk factors. Ethnic disparities in hospitalization and death due to pH1N1 were noted. The purpose of this study is to determine whether there are ethnic disparities in acquiring the 2009 pandemic H1N1.
Methods
We conducted a test-negative case–control study of the risk of pH1N1 infection using data from Ontario, Canada. Cases were laboratory confirmed to have influenza using reverse-transcriptase polymerase chain reaction (RT-PCR), and controls were obtained from the same population and were RT-PCR negative. Multivariate logistic regression was used to determine the association between ethnicity and pH1N1 infection, while adjusting for demographic, clinical and ecological covariates.
Results
Adult cases were more likely than controls to be self-classified as East/Southeast Asian (OR = 2.59, 95% CI 1.02-6.57), South Asian (OR = 6.22, 95% CI 2.01-19.24) and Black (OR = 9.72, 95% CI 2.29-41.27). Pediatric cases were more likely to be self-identified as Black (OR = 6.43, 95% CI 1.83-22.59). However, pediatric cases without risk factors for severe influenza infection were more likely to be South Asian (OR 2.92, 95% CI 1.11-7.68), Black (OR 16.02, 95% CI 2.85-89.92), and West Asian/Arab, Latin American or Multi-racial groups (OR 3.09 95% CI 1.06-9.00).
Conclusions
pH1N1 cases were more likely to come from certain ethnic groups compared to test-negative controls. Insights into whether these disparities arise due to social or biological factors are needed in order to understand what approaches can be taken to reduce the burden of a future influenza pandemic.
doi:10.1186/1471-2458-14-214
PMCID: PMC3942768  PMID: 24580862
Influenza; Ethnicity; Epidemiology
5.  Association between Birth Order and Emergency Room Visits and Acute Hospital Admissions following Pediatric Vaccination: A Self-Controlled Study 
PLoS ONE  2013;8(12):e81070.
Objective
We investigated the association between a child's birth order and emergency room (ER) visits and hospital admissions following 2-,4-,6- and 12-month pediatric vaccinations.
Methods
We included all children born in Ontario between April 1st, 2006 and March 31st, 2009 who received a qualifying vaccination. We identified vaccinations, ER visits and admissions using health administrative data housed at the Institute for Clinical Evaluative Sciences. We used the self-controlled case series design to compare the relative incidence (RI) of events among 1st-born and later-born children using relative incidence ratios (RIR).
Results
For the 2-month vaccination, the RIR for 1st-borns versus later-born children was 1.37 (95% CI: 1.19–1.57), which translates to 112 additional events/100,000 vaccinated. For the 4-month vaccination, the RIR for 1st-borns vs. later-borns was 1.70 (95% CI: 1.45–1.99), representing 157 additional events/100,000 vaccinated. At 6 months, the RIR for 1st vs. later-borns was 1.27 (95% CI: 1.09–1.48), or 77 excess events/100,000 vaccinated. At the 12-month vaccination, the RIR was 1.11 (95% CI: 1.02–1.21), or 249 excess events/100,000 vaccinated.
Conclusions
Birth order is associated with increased incidence of ER visits and hospitalizations following vaccination in infancy. 1st-born children had significantly higher relative incidence of events compared to later-born children.
doi:10.1371/journal.pone.0081070
PMCID: PMC3852020  PMID: 24324662
6.  New Estimates of Incidence of Encephalitis in England 
Emerging Infectious Diseases  2013;19(9):1455-1462.
Encephalitis causes high rates of illness and death, yet its epidemiology remains poorly understood. To improve incidence estimates in England and inform priority setting and treatment and prevention strategies, we used hospitalization data to estimate incidence of infectious and noninfectious encephalitis during 2005–2009. Hospitalization data were linked to a dataset of extensively investigated cases of encephalitis from a prospective study, and capture–recapture models were applied. Incidence was estimated from unlinked hospitalization data as 4.32 cases/100,000 population/year. Capture–recapture models gave a best estimate of encephalitis incidence of 5.23 cases/100,000/year, although the models’ indicated incidence could be as high as 8.66 cases/100,000/year. This analysis indicates that the incidence of encephalitis in England is considerably higher than previously estimated. Therefore, encephalitis should be a greater priority for clinicians, researchers, and public health officials.
doi:10.3201/eid1909.130064
PMCID: PMC3810913  PMID: 23969035
encephalitis; incidence studies; viral infections; autoimmune diseases; acute disseminated encephalomyelitis; neurological; viruses
7.  Rubella immunity among prenatal women in Ontario, 2006–2010 
BMC Infectious Diseases  2013;13:362.
Background
Countries of the Americas have been working towards rubella elimination since 2003 and endemic rubella virus transmission appears to have been interrupted since 2009. To contribute towards monitoring of rubella elimination, we assessed rubella seroprevalence among prenatal screening tests performed in Ontario.
Methods
Specimens received for prenatal rubella serologic testing at the Public Health Ontario Laboratory, the provincial reference laboratory, between 2006 and 2010 were analyzed. A patient-based dataset was created using all tests occurring among 15–49 year-old females, where prenatal screening was indicated. Multiple tests were assigned to the same patient on the basis of health card number, name and date of birth. Only unique tests performed at least nine months apart were included. SAS version 9.2 was used for analysis.
Results
Between 2006 and 2010, we identified 459,963 women who underwent 551,160 unique prenatal screening tests for rubella. Of these, 81.6%, 17.1% and 1.4% had one, two and three or more tests respectively.
Rubella immunity remained stable at approximately 90% overall; the proportion of susceptible women was 4.4%. Additionally, 0.6% of women were initially susceptible and subsequently developed immunity. Across the province, susceptibility was highest in the north and declined with increasing age (p < 0.0001). Among women with multiple tests, the proportion who remained susceptible declined as the number of years between tests increased (p < .0001). Based on age at first test, younger women had the highest susceptibility (4.2% among 15–19 year-olds) and were significantly more likely to develop immunity if previously susceptible (p < .0001).
Conclusion
Rubella susceptibility among prenatal women in Ontario supports elimination goals as population immunity in this group is relatively high. Higher susceptibility among young women and women living in the north highlights an opportunity for greater focus on identification and immunization of susceptible women in these groups.
doi:10.1186/1471-2334-13-362
PMCID: PMC3735453  PMID: 23914729
Rubella; Seroprevalence study; Prenatal screening; Rubella elimination goals; Ontario; Canada
8.  Vaccine Effectiveness Against Laboratory-Confirmed Influenza Hospitalizations Among Elderly Adults During the 2010–2011 Season 
Although the benefits of influenza vaccines for preventing serious influenza outcomes in elderly adults are uncertain, the results of this study suggest that the 2010–2011 influenza vaccine was 42% effective in reducing laboratory-confirmed influenza hospitalizations in this high-risk population.
Background. Although annual influenza immunization is recommended for adults aged ≥65 years due to the substantial burden of illness, the evidence base for this recommendation is weak. Prior observational studies that examined influenza vaccine effectiveness against nonspecific serious outcomes suffered from selection bias and the lack of laboratory confirmation for influenza infection. The objective of this study was to determine the effectiveness of the 2010–2011 seasonal influenza vaccine against laboratory-confirmed influenza hospitalizations among community-dwelling elderly adults, a serious and highly specific outcome.
Methods. We conducted a test-negative study of community-dwelling adults aged >65 years in Ontario, Canada. Respiratory specimens collected between 1 December 2010 and 30 April 2011 from patients admitted to acute care hospitals were tested for influenza using nucleic acid amplification techniques. Influenza vaccination was ascertained from physician billing claims through linkage to health administrative datasets.
Results. Receipt of the 2010–2011 seasonal influenza vaccine was associated with a 42% (95% confidence interval, 29%–53%) reduction in laboratory-confirmed influenza hospitalizations. Vaccine effectiveness estimates were consistent across age groups, by sex, and regardless of outcome severity, timing of testing, and when considering individuals vaccinated <7 or <14 days prior to admission as unvaccinated.
Conclusions. Results of this study will better inform decision making regarding influenza vaccination of elderly adults. Similar analyses are needed annually due to antigenic drift and frequent changes in influenza vaccine composition. The linkage of routinely collected laboratory testing and health administrative data represents an efficient method for estimating influenza vaccine effectiveness that complements prospective studies.
doi:10.1093/cid/cit404
PMCID: PMC3749748  PMID: 23788243
influenza vaccine; hospitalization; vaccine effectiveness; elderly adults
9.  Contagious Comments: What Was the Online Buzz About the 2011 Quebec Measles Outbreak? 
PLoS ONE  2013;8(5):e64072.
Background
Although interruption of endemic measles was achieved in the Americas in 2002, Quebec experienced an outbreak in 2011 of 776 reported cases; 80% of these individuals had not been fully vaccinated. We analyzed readers’ online responses to Canadian news articles regarding the outbreak to better understand public perceptions of measles and vaccination.
Methods
We searched Canadian online English and French news sites for articles posted between April 2011 and March 2012 containing the words “measles” and “Quebec”. We included articles that i) concerned the outbreak or related vaccination strategies; and ii) generated at least ten comments. Two English and two bilingual researchers coded the unedited comments, categorizing codes to allow themes to emerge.
Results
We analyzed 448 comments from 188 individuals, in response to three French articles and six English articles; 112 individuals expressed positive perceptions of measles vaccination (2.2 comments/person), 38 were negative (4.2 comments/person), 11 had mixed feelings (1.5 comments/person), and 27 expressed no opinion (1.1 comments/person). Vaccine-supportive themes involved the success of vaccination in preventing disease spread, societal responsibility to vaccinate for herd immunity, and refutation of the autism link. Those against measles vaccination felt it was a personal rather than societal choice, and conveyed a distrust of vaccine manufacturers, believing that measles infection is not only safe but safer than vaccination. Commenters with mixed feelings expressed uncertainty of the infection’s severity, and varied in support of all vaccines based on perceived risk/benefit ratios.
Conclusion
The anti-vaccine minority’s volume of comments translates to a disproportionately high representation on online boards. Public health messages should address concerns by emphasizing that immunization is always a personal choice in Canada, and that the pharmaceutical industry is strictly controlled. Illustrating the dangers of measles through personal stories, rather than scientific data only, may also serve to strengthen messaging.
doi:10.1371/journal.pone.0064072
PMCID: PMC3654905  PMID: 23691152
11.  Human papilloma virus vaccination programs reduce health inequity in most scenarios: a simulation study 
BMC Public Health  2012;12:935.
Background
The global and within-country epidemiology of cervical cancer exemplifies health inequity. Public health programs may reduce absolute risk but increase inequity; inequity may be further compounded by screening programs. In this context, we aimed to explore what the impact of human papillomavirus (HPV) vaccine might have on health equity allowing for uncertainty surrounding the long-term effect of HPV vaccination programs.
Methods
A simple static multi-way sensitivity analysis was carried out to compare the relative risk, comparing after to before implementation of a vaccination program, of infections which would cause invasive cervical cancer if neither prevented nor detected, using plausible ranges of vaccine effectiveness, vaccination coverage, screening sensitivity, screening uptake and changes in uptake.
Results
We considered a total number of 3,793,902 scenarios. In 63.9% of scenarios considered, vaccination would lead to a better outcome for a population or subgroup with that combination of parameters. Regardless of vaccine effectiveness and coverage, most simulations led to lower rates of disease.
Conclusions
If vaccination coverage and screening uptake are high, then communities are always better off with a vaccination program. The findings highlight the importance of achieving and maintaining high immunization coverage and screening uptake in high risk groups in the interest of health equity.
doi:10.1186/1471-2458-12-935
PMCID: PMC3529110  PMID: 23113881
12.  The use of syndromic surveillance for decision-making during the H1N1 pandemic: A qualitative study 
BMC Public Health  2012;12:929.
Background
Although an increasing number of studies are documenting uses of syndromic surveillance by front line public health, few detail the value added from linking syndromic data to public health decision-making. This study seeks to understand how syndromic data informed specific public health actions during the 2009 H1N1 pandemic.
Methods
Semi-structured telephone interviews were conducted with participants from Ontario’s public health departments, the provincial ministry of health and federal public health agency to gather information about syndromic surveillance systems used and the role of syndromic data in informing specific public health actions taken during the pandemic. Responses were compared with how the same decisions were made by non-syndromic surveillance users.
Results
Findings from 56 interviews (82% response) show that syndromic data were most used for monitoring virus activity, measuring impact on the health care system and informing the opening of influenza assessment centres in several jurisdictions, and supporting communications and messaging, rather than its intended purpose of early outbreak detection. Syndromic data had limited impact on decisions that involved the operation of immunization clinics, school closures, sending information letters home with school children or providing recommendations to health care providers. Both syndromic surveillance users and non-users reported that guidance from the provincial ministry of health, communications with stakeholders and vaccine availability were driving factors in these public health decisions.
Conclusions
Syndromic surveillance had limited use in decision-making during the 2009 H1N1 pandemic in Ontario. This study provides insights into the reasons why this occurred. Despite this, syndromic data were valued for providing situational awareness and confidence to support public communications and recommendations. Developing an understanding of how syndromic data are utilized during public health events provides valuable evidence to support future investments in public health surveillance.
doi:10.1186/1471-2458-12-929
PMCID: PMC3539916  PMID: 23110473
Decision making; Pandemic influenza; Public health; Surveillance; Syndromic surveillance
13.  Influenza vaccination coverage across ethnic groups in Canada 
Background:
The success of influenza vaccination campaigns may be suboptimal if subgroups of the population face unique barriers or have misconceptions about vaccination. We conducted a national study to estimate influenza vaccine coverage across 12 ethnic groups in Canada to assess the presence of ethnic disparities.
Methods:
We pooled responses to the Canadian Community Health Survey between 2003 and 2009 (n = 437 488). We estimated ethnicity-specific self-reported influenza vaccine coverage for the overall population, for people aged 65 years and older, and for people aged 12–64 years with and without chronic conditions. We used weighted logistic regression models to examine the association between ethnicity and influenza vaccination, adjusting for sociodemographic factors and health status.
Results:
Influenza vaccination coverage ranged from 25% to 41% across ethnic groups. After adjusting for sociodemographic factors and health status for people aged 12 years and older, all ethnic groups were more likely to have received a vaccination against influenza than people who self-identified as white, with the exception of those who self-identified as black (odds ratio [OR] 1.01, 95% confidence interval [CI] 0.88–1.15). Compared with white Canadians, Canadians of Filipino (OR 2.00, 95% CI 1.67–2.40) and Southeast Asian (OR 1.66, 95% CI 1.36–2.03) descent had the greatest likelihood of having received vaccination against influenza.
Interpretation:
Influenza vaccine coverage in Canada varies by ethnicity. Black and white Canadians have the lowest uptake of influenza vaccine of the ethnic groups represented in our study. Further research is needed to understand the facilitators, barriers and misconceptions relating to vaccination that exist across ethnic groups, and to identify promotional strategies that may improve uptake among black and white Canadians.
doi:10.1503/cmaj.111628
PMCID: PMC3478352  PMID: 22966054
14.  The Impact of Infection on Population Health: Results of the Ontario Burden of Infectious Diseases Study 
PLoS ONE  2012;7(9):e44103.
Background
Evidence-based priority setting is increasingly important for rationally distributing scarce health resources and for guiding future health research. We sought to quantify the contribution of a wide range of infectious diseases to the overall infectious disease burden in a high-income setting.
Methodology/Principal Findings
We used health-adjusted life years (HALYs), a composite measure comprising premature mortality and reduced functioning due to disease, to estimate the burden of 51 infectious diseases and associated syndromes in Ontario using 2005–2007 data. Deaths were estimated from vital statistics data and disease incidence was estimated from reportable disease, healthcare utilization, and cancer registry data, supplemented by local modeling studies and national and international epidemiologic studies. The 51 infectious agents and associated syndromes accounted for 729 lost HALYs, 44.2 deaths, and 58,987 incident cases per 100,000 population annually. The most burdensome infectious agents were: hepatitis C virus, Streptococcus pneumoniae, Escherichia coli, human papillomavirus, hepatitis B virus, human immunodeficiency virus, Staphylococcus aureus, influenza virus, Clostridium difficile, and rhinovirus. The top five, ten, and 20 pathogens accounted for 46%, 67%, and 75% of the total infectious disease burden, respectively. Marked sex-specific differences in disease burden were observed for some pathogens. The main limitations of this study were the exclusion of certain infectious diseases due to data availability issues, not considering the impact of co-infections and co-morbidity, and the inability to assess the burden of milder infections that do not result in healthcare utilization.
Conclusions/Significance
Infectious diseases continue to cause a substantial health burden in high-income settings such as Ontario. Most of this burden is attributable to a relatively small number of infectious agents, for which many effective interventions have been previously identified. Therefore, these findings should be used to guide public health policy, planning, and research.
doi:10.1371/journal.pone.0044103
PMCID: PMC3433488  PMID: 22962601
15.  Epidemiology of serogroup B invasive meningococcal disease in Ontario, Canada, 2000 to 2010 
BMC Infectious Diseases  2012;12:202.
Background
Invasive meningococcal disease (IMD) caused by serogroup B is the last major serogroup in Canada to become vaccine-preventable. The anticipated availability of vaccines targeting this serogroup prompted an assessment of the epidemiology of serogroup B disease in Ontario, Canada.
Methods
We retrieved information on confirmed IMD cases reported to Ontario’s reportable disease database between January 1, 2000 and December 31, 2010 and probabilistically-linked these cases to Public Health Ontario Laboratory records. Rates were calculated with denominator data obtained from Statistics Canada. We calculated a crude number needed to vaccinate using the inverse of the infant (<1 year) age-specific incidence multiplied by expected vaccine efficacies between 70% and 80%, and assuming only direct protection (no herd effects).
Results
A total of 259 serogroup B IMD cases were identified in Ontario over the 11-year period. Serogroup B was the most common cause of IMD. Incidence ranged from 0.11 to 0.27/100,000/year, and fluctuated over time. Cases ranged in age from 13 days to 101 years; 21.4% occurred in infants, of which 72.7% were <6 months. Infants had the highest incidence (3.70/100,000). Case-fatality ratio was 10.7% overall. If we assume that all infant cases would be preventable by vaccination, we would need to vaccinate between 33,784 and 38,610 infants to prevent one case of disease.
Conclusions
Although rare, the proportion of IMD caused by serogroup B has increased and currently causes most IMD in Ontario, with infants having the highest risk of disease. Although serogroup B meningococcal vaccines are highly anticipated, our findings suggest that decisions regarding publicly funding serogroup B meningococcal vaccines will be difficult and may not be based on disease burden alone.
doi:10.1186/1471-2334-12-202
PMCID: PMC3472197  PMID: 22928839
Invasive meningococcal disease; Neisseria meningitidis; Serogroup B; Epidemiology; Surveillance; Ontario; Canada
16.  The potential effect of temporary immunity as a result of bias associated with healthy users and social determinants on observations of influenza vaccine effectiveness; could unmeasured confounding explain observed links between seasonal influenza vaccine and pandemic H1N1 infection? 
BMC Public Health  2012;12:458.
Background
Five observational studies from Canada found an association between seasonal influenza vaccine receipt and increased risk of pandemic influenza H1N1 2009 infection. This association remains unexplained. Although uncontrolled confounding has been suggested as a possible explanation, the nature of such confounding has not been identified. Observational studies of influenza vaccination can be affected by confounding due to healthy users and the influence of social determinants on health. The purpose of this study was to investigate the influence that these two potential confounders may have in combination with temporary immunity, using stratified tables. The hypothesis is that respiratory virus infections may activate a temporary immunity that provides short-term non-specific protection against influenza and that the relationship with being a healthy user or having a social determinant may result in confounding.
Methods
We simulated the effect of confounding on vaccine effectiveness assuming that this could result from both social determinants and healthy user effects as they both influence the risk of seasonal influenza and non-influenza respiratory virus infections as well as the likelihood of being vaccinated. We then examined what impact this may have had on measurement of seasonal influenza vaccine effectiveness against pandemic influenza.
Results
In this simulation, failure to adjust for healthy users and social determinants would result in an erroneously increased risk of pandemic influenza infection associated with seasonal influenza vaccination. The effect sizes were not however large.
Conclusions
We found that unmeasured healthy user effects and social determinants could result in an apparent association between seasonal influenza vaccine and pandemic influenza infection by virtue of being related to temporary immunity. Adjustment for social determinants of health and the healthy user effects are required in order to improve the quality of observational studies of influenza vaccine effectiveness.
doi:10.1186/1471-2458-12-458
PMCID: PMC3490826  PMID: 22716096
Influenza; Influenza vaccination; Confounding; Epidemiology
17.  The epidemiology of travel-related Salmonella Enteritidis in Ontario, Canada, 2010–2011 
BMC Public Health  2012;12:310.
Background
Increases in the number of salmonellosis cases due to Salmonella Enteritidis (SE) in 2010 and 2011 prompted a public health investigation in Ontario, Canada. In this report, we describe the current epidemiology of travel-related (TR) SE, compare demographics, symptoms and phage types (PTs) of TR and domestically-acquired (DA) cases, and estimate the odds of acquiring SE by region of the world visited.
Methods
All incident cases of culture confirmed SE in Ontario obtained from isolates and specimens submitted to public health laboratories were included in this study. Demographic and illness characteristics of TR and DA cases were compared. A national travel survey was used to provide estimates for the number of travellers to various destinations to approximate rates of SE in travellers. Multivariate logistic regression was used to estimate the odds of acquiring SE when travelling to various world regions.
Results
Overall, 51.9% of SE cases were TR during the study period. This ranged from 35.7% TR cases in the summer travel period to 65.1% TR cases in the winter travel period. Compared to DA cases, TR cases were older and were less likely to seek hospital care. For Ontario travellers, the adjusted odds of acquiring SE was the highest for the Caribbean (OR 37.29, 95% CI 17.87-77.82) when compared to Europe. Certain PTs were more commonly associated with travel (e.g., 1, 4, 5b, 7a, Atypical) than with domestic infection. Of the TR cases, 88.9% were associated with travel to the Caribbean and Mexico region, of whom 90.1% reported staying on a resort. Within this region, there were distinct associations between PTs and countries.
Conclusions
There is a large burden of TR illness from SE in Ontario. Accurate classification of cases by travel history is important to better understand the source of infections. The findings emphasize the need to make travellers, especially to the Caribbean, and health professionals who provide advice to travellers, aware of this risk. The findings may be generalized to other jurisdictions with travel behaviours in their residents similar to Ontario residents.
doi:10.1186/1471-2458-12-310
PMCID: PMC3356229  PMID: 22537320
18.  Determining Mortality Rates Attributable to Clostridium difficile Infection 
Emerging Infectious Diseases  2012;18(2):305-307.
To determine accuracy of measures of deaths attributable to Clostridium difficile infection, we compared 3 measures for 2007–2008 in Ontario, Canada: death certificate; death within 30 days of infection; and panel review. Data on death within 30 days were more feasible than panel review and more accurate than death certificate data.
doi:10.3201/eid1802.101611
PMCID: PMC3310441  PMID: 22305427
Clostridium difficile; mortality; mortality rates; deaths; death certificates; panel review; Ontario; Canada
19.  Diphtheria in the Postepidemic Period, Europe, 2000–2009 
Emerging Infectious Diseases  2012;18(2):217-225.
Efforts must be made to maintain high vaccination coverage.
Diphtheria incidence has decreased in Europe since its resurgence in the 1990s, but circulation continues in some countries in eastern Europe, and sporadic cases have been reported elsewhere. Surveillance data from Diphtheria Surveillance Network countries and the World Health Organization European Region for 2000–2009 were analyzed. Latvia reported the highest annual incidence in Europe each year, but the Russian Federation and Ukraine accounted for 83% of all cases. Over the past 10 years, diphtheria incidence has decreased by >95% across the region. Although most deaths occurred in disease-endemic countries, case-fatality rates were highest in countries to which diphtheria is not endemic, where unfamiliarity can lead to delays in diagnosis and treatment. In western Europe, toxigenic Corynebacterium ulcerans has increasingly been identified as the etiologic agent. Reduction in diphtheria incidence over the past 10 years is encouraging, but maintaining high vaccination coverage is essential to prevent indigenous C. ulcerans and reemergence of C. diphtheriae infections.
doi:10.3201/eid1802.110987
PMCID: PMC3310452  PMID: 22304732
diphtheria; Corynebacterium diphtheriae; Corynebacterium ulcerans; bacteria; toxin; surveillance; immunization; vaccination; pseudomembrane; antitoxin; epidemiology; Europe
20.  Adverse Events following 12 and 18 Month Vaccinations: a Population-Based, Self-Controlled Case Series Analysis 
PLoS ONE  2011;6(12):e27897.
Background
Live vaccines have distinct safety profiles, potentially causing systemic reactions one to 2 weeks after administration. In the province of Ontario, Canada, live MMR vaccine is currently recommended at age 12 months and 18 months.
Methods
Using the self-controlled case series design we examined 271,495 12 month vaccinations and 184,312 18 month vaccinations to examine the relative incidence of the composite endpoint of emergency room visits or hospital admissions in consecutive one day intervals following vaccination. These were compared to a control period 20 to 28 days later. In a post-hoc analysis we examined the reasons for emergency room visits and the average acuity score at presentation for children during the at-risk period following the 12 month vaccine.
Results
Four to 12 days post 12 month vaccination, children had a 1.33 (1.29–1.38) increased relative incidence of the combined endpoint compared to the control period, or at least one event during the risk interval for every 168 children vaccinated. Ten to 12 days post 18 month vaccination, the relative incidence was 1.25 (95%, 1.17–1.33) which represented at least one excess event for every 730 children vaccinated. The primary reason for increased events was statistically significant elevations in emergency room visits following all vaccinations. There were non-significant increases in hospital admissions. There were an additional 20 febrile seizures for every 100,000 vaccinated at 12 months.
Conclusions
There are significantly elevated risks of primarily emergency room visits approximately one to two weeks following 12 and 18 month vaccination. Future studies should examine whether these events could be predicted or prevented.
doi:10.1371/journal.pone.0027897
PMCID: PMC3236196  PMID: 22174753
21.  Humoral and Cell-Mediated Immunity to Pandemic H1N1 Influenza in a Canadian Cohort One Year Post-Pandemic: Implications for Vaccination 
PLoS ONE  2011;6(11):e28063.
We evaluated a cohort of Canadian donors for T cell and antibody responses against influenza A/California/7/2009 (pH1N1) at 8-10 months after the 2nd pandemic wave by flow cytometry and microneutralization assays. Memory CD8 T cell responses to pH1N1 were detectable in 58% (61/105) of donors. These responses were largely due to cross-reactive CD8 T cell epitopes as, for those donors tested, similar recall responses were obtained to A/California 2009 and A/PR8 1934 H1N1 Hviruses. Longitudinal analysis of a single infected individual showed only a small and transient increase in neutralizing antibody levels, but a robust CD8 T cell response that rose rapidly post symptom onset, peaking at 3 weeks, followed by a gradual decline to the baseline levels seen in a seroprevalence cohort post-pandemic. The magnitude of the influenza-specific CD8 T cell memory response at one year post-pandemic was similar in cases and controls as well as in vaccinated and unvaccinated donors, suggesting that any T cell boosting from infection was transient. Pandemic H1-specific antibodies were only detectable in approximately half of vaccinated donors. However, those who were vaccinated within a few months following infection had the highest persisting antibody titers, suggesting that vaccination shortly after influenza infection can boost or sustain antibody levels. For the most part the circulating influenza-specific T cell and serum antibody levels in the population at one year post-pandemic were not different between cases and controls, suggesting that natural infection does not lead to higher long term T cell and antibody responses in donors with pre-existing immunity to influenza. However, based on the responses of one longitudinal donor, it is possible for a small population of pre-existing cross-reactive memory CD8 T cells to expand rapidly following infection and this response may aid in viral clearance and contribute to a lessening of disease severity.
doi:10.1371/journal.pone.0028063
PMCID: PMC3223223  PMID: 22132212
22.  Seroprevalence of Pandemic Influenza H1N1 in Ontario from January 2009–May 2010 
PLoS ONE  2011;6(11):e26427.
Background
We designed a seroprevalence study using multiple testing assays and population sources to estimate the community seroprevalence of pH1N1/09 and risk factors for infection before the outbreak was recognized and throughout the pandemic to the end of 2009/10 influenza season.
Methods
Residual serum specimens from five time points (between 01/2009 and 05/2010) and samples from two time points from a prospectively recruited cohort were included. The distribution of risk factors was explored in multivariate adjusted analyses using logistic regression among the cohort. Antibody levels were measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays.
Results
Residual sera from 3375 patients and 1024 prospectively recruited cohort participants were analyzed. Pre-pandemic seroprevalence ranged from 2%–12% across age groups. Overall seropositivity ranged from 10%–19% post-first wave and 32%–41% by the end of the 2009/10 influenza season. Seroprevalence and risk factors differed between MN and HAI assays, particularly in older age groups and between waves. Following the H1N1 vaccination program, higher GMT were noted among vaccinated individuals. Overall, 20–30% of the population was estimated to be infected.
Conclusions
Combining population sources of sera across five time points with prospectively collected epidemiological information yielded a complete description of the evolution of pH1N1 infection.
doi:10.1371/journal.pone.0026427
PMCID: PMC3215698  PMID: 22110586
23.  Potential risk factors associated with human encephalitis: application of canonical correlation analysis 
Background
Infection of the CNS is considered to be the major cause of encephalitis and more than 100 different pathogens have been recognized as causative agents. Despite being identified worldwide as an important public health concern, studies on encephalitis are very few and often focus on particular types (with respect to causative agents) of encephalitis (e.g. West Nile, Japanese, etc.). Moreover, a number of other infectious and non-infectious conditions present with similar symptoms, and distinguishing encephalitis from other disguising conditions continues to a challenging task.
Methods
We used canonical correlation analysis (CCA) to assess associations between set of exposure variable and set of symptom and diagnostic variables in human encephalitis. Data consists of 208 confirmed cases of encephalitis from a prospective multicenter study conducted in the United Kingdom. We used a covariance matrix based on Gini's measure of similarity and used permutation based approaches to test significance of canonical variates.
Results
Results show that weak pair-wise correlation exists between the risk factor (exposure and demographic) and symptom/laboratory variables. However, the first canonical variate from CCA revealed strong multivariate correlation (ρ = 0.71, se = 0.03, p = 0.013) between the two sets. We found a moderate correlation (ρ = 0.54, se = 0.02) between the variables in the second canonical variate, however, the value is not statistically significant (p = 0.68). Our results also show that a very small amount of the variation in the symptom sets is explained by the exposure variables. This indicates that host factors, rather than environmental factors might be important towards understanding the etiology of encephalitis and facilitate early diagnosis and treatment of encephalitis patients.
Conclusions
There is no standard laboratory diagnostic strategy for investigation of encephalitis and even experienced physicians are often uncertain about the cause, appropriate therapy and prognosis of encephalitis. Exploration of human encephalitis data using advanced multivariate statistical modelling approaches that can capture the inherent complexity in the data is, therefore, crucial in understanding the causes of human encephalitis. Moreover, application of multivariate exploratory techniques will generate clinically important hypotheses and offer useful insight into the number and nature of variables worthy of further consideration in a confirmatory statistical analysis.
doi:10.1186/1471-2288-11-120
PMCID: PMC3189172  PMID: 21859458
24.  An assessment of mumps vaccine effectiveness by dose during an outbreak in Canada 
Background
This investigation was done to assess vaccine effectiveness of one and two doses of the measles, mumps and rubella (MMR) vaccine during an outbreak of mumps in Ontario. The level of coverage required to reach herd immunity and interrupt community transmission of mumps was also estimated.
Methods
Information on confirmed cases of mumps was retrieved from Ontario’s integrated Public Health Information System. Cases that occurred between Sept. 1, 2009, and June 10, 2010, were included. Selected health units supplied coverage data from the Ontario Immunization Record Information System. Vaccine effectiveness by dose was calculated using the screening method. The basic reproductive number (R0) represents the average number of new infections per case in a fully susceptile population, and R0 values of between 4 and 10 were considered for varying levels of vaccine effectiveness.
Results
A total of 134 confirmed cases of mumps were identified. Information on receipt of MMR vaccine was available for 114 (85.1%) cases, of whom 63 (55.3%) reported having received only one dose of vaccine; 32 (28.1%) reported having received two doses. Vaccine effectiveness of one dose of the MMR vaccine ranged from 49.2% to 81.6%, whereas vaccine effectiveness of two doses ranged from 66.3% to 88.0%. If we assume vaccine effectiveness of 85% for two doses of the vaccine, vaccine coverage of 88.2% and 98.0% would be needed to interrupt community transmission of mumps if the corresponding reproductive values were four and six.
Interpretation
Our estimates of vaccine effectiveness of one and two doses of mumps-containing vaccine were consistent with the estimates that have been reported in other outbreaks. Outbreaks occurring in Ontario and elsewhere serve as a warning against complacency over vaccination programs.
doi:10.1503/cmaj.101371
PMCID: PMC3114893  PMID: 21576295
25.  Estimating background rates of Guillain-Barré Syndrome in Ontario in order to respond to safety concerns during pandemic H1N1/09 immunization campaign 
BMC Public Health  2011;11:329.
Background
The province of Ontario, Canada initiated mass immunization clinics with adjuvanted pandemic H1N1 influenza vaccine in October 2009. Due to the scale of the campaign, temporal associations with Guillain-Barré syndrome (GBS) and vaccination were expected. The objectives of this analysis were to estimate the number of background GBS cases expected to occur in the projected vaccinated population and to estimate the number of additional GBS cases which would be expected if an association with vaccination existed. The number of influenza-associated GBS cases was also determined.
Methods
Baseline incidence rates of GBS were determined from published Canadian studies and applied to projected vaccine coverage data to estimate the expected number of GBS cases in the vaccinated population. Assuming an association with vaccine existed, the number of additional cases of GBS expected was determined by applying the rates observed during the 1976 Swine Flu and 1992/1994 seasonal influenza campaigns in the United States. The number of influenza-associated GBS cases expected to occur during the vaccination campaign was determined based on risk estimates of GBS after influenza infection and provincial influenza infection rates using a combination of laboratory-confirmed cases and data from a seroprevalence study.
Results
The overall provincial vaccine coverage was estimated to be between 32% and 38%. Assuming 38% coverage, between 6 and 13 background cases of GBS were expected within this projected vaccinated cohort (assuming 32% coverage yielded between 5-11 background cases). An additional 6 or 42 cases would be expected if an association between GBS and influenza vaccine was observed (assuming 32% coverage yielded 5 or 35 additional cases); while up to 31 influenza-associated GBS cases could be expected to occur. In comparison, during the same period, only 7 cases of GBS were reported among vaccinated persons.
Conclusions
Our analyses do not suggest an increased number of GBS cases due to the vaccine. Awareness of expected rates of GBS is crucial when assessing adverse events following influenza immunization. Furthermore, since individuals with influenza infection are also at risk of developing GBS, they must be considered in such analyses, particularly if the vaccine campaign and disease are occurring concurrently.
doi:10.1186/1471-2458-11-329
PMCID: PMC3112136  PMID: 21586163

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