Real-world influenza vaccine effectiveness:New designs and methods to adjust for confounding and bias

Zoals aanbevolen door de Wereldgezondheidsorganisatie (WHO), is jaarlijkse influenzavaccinatie van groepen met een verhoogd risico op complicaties ten gevolge van een influenza-infectie zoals ouderen en personen met bepaalde medische risicofactoren een van de belangrijkste preventieve maatregelen. In de praktijk is de influenzavaccinatiegraad echter doorgaans laag. Onzekerheid over de werkelijke effectiviteit van het influenzavaccin kan hiervoor de oorzaak zijn. Zowel beperkingen bij het opzetten van gerandomiseerd (placebo)gecontroleerd onderzoek als de gevoeligheid van observationeel onderzoek voor vertekening door verschillende vormen van bias of confounding, kunnen bijdragen aan deze onzekerheid. In dit proefschrift zijn nieuwe onderzoeksopzetten en methoden gebruikt om een meer valide schatting te maken van de influenzavaccinatie effectiviteit (IVE). Hierbij is rekening gehouden met potentiële bias en confounding en zijn de IVE schattingen hiervoor gecorrigeerd. Na correctie voor verschillende soorten bias en potentiële confounders, vonden wij dat influenzavaccinatie redelijk effectief was tegen influenza en complicaties gerelateerd aan influenza. Daarnaast signaleerden wij dat conventionele methoden voor meta-analyses mogelijk niet het beste instrument zijn om de gepoolde IVE te meten en dat het gebruik van betrouwbaardere methoden overwogen moeten worden bij toekomstige studies. Tot slot namen wij, afhankelijk van influenza virus (sub)typen, influenza seizoen en het type controlegroep dat geïncludeerd was in het test-negative design case-control onderzoek, extreme variabiliteit waar tussen de IVE schattingen

Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014:The test-negative design case-control study with different control groups

Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE estimates. We have conducted a TND study using the Dutch Sentinel Practices of NIVEL Primary Care Database which includes data from patients who consulted the General Practitioner (GP) for an episode of acute influenza-like illness (ILI) or acute respiratory infection (ARI) with known influenza vaccination status. Cases were patients tested positive for influenza virus. Controls were grouped into those who tested (1) negative for influenza virus (all influenza negative), (2) negative for influenza virus, but positive for respiratory syncytial virus, rhinovirus or enterovirus (non-influenza virus positive), and (3) negative for these four viruses (pan-negative). We estimated the IVE over all epidemic seasons from 2003/2004 through 2013/2014, pooled IVE for influenza vaccine partial/full matched and mismatched seasons and the individual seasons using generalized linear mixed-effect and multiple logistic regression models. The overall IVE adjusted for age, GP ILI/ARI diagnosis, chronic disease and respiratory allergy was 35% (95% CI: 15-48), 64% (95% CI: 49-75) and 21% (95% CI: -1 to 39) for all influenza negative, non-influenza virus positive and pan-negative controls, respectively. In both the main and subgroup analyses IVE estimates were the highest using non-influenza virus positive controls, likely due to limiting inclusion of controls without laboratory-confirmation of a virus causing the respiratory disease

Hepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort.

BACKGROUND & AIMS: Direct-acting antiviral therapies (DAA) are an important tool for hepatitis C virus (HCV) elimination. However, reinfection among people who inject drugs (PWID) may hamper elimination targets. Therefore, we estimated HCV reinfection rates among DAA-treated individuals, including PWID. METHODS: We analyzed data from the British Columbia Hepatitis Testers Cohort which included ∼1.7 million individuals screened for HCV in British Columbia, Canada. We followed HCV-infected individuals treated with DAAs who achieved a sustained virologic response (SVR) and had ≥1 subsequent HCV RNA measurement to April 22nd, 2018. Reinfection was defined as a positive RNA measurement after SVR. PWID were identified using a validated algorithm and classified based on recent (<3 years) or former (≥3 years before SVR) use. Crude reinfection rates per 100 person-years (PYs) were calculated. Poisson regression was used to model adjusted incidence rate ratios (IRRs) and 95% CIs. RESULTS: Of 4,114 individuals who met the inclusion criteria, most were male (n = 2,692, 65%), born before 1965 (n = 3,411, 83%) and were either recent (n = 875, 21%) or former PWID (n = 1,793, 44%). Opioid-agonist therapy (OAT) was received by 19% of PWID. We identified 40 reinfections during 2,767 PYs. Reinfection rates were higher among recent (3.1/100 PYs; IRR 6.7; 95% CI 1.9-23.5) and former PWID (1.4/100 PYs; IRR 3.7; 95% CI 1.1-12.9) than non-PWID (0.3/100 PYs). Among recent PWID, reinfection rates were higher among individuals born after 1975 (10.2/100 PYs) and those co-infected with HIV (5.7/100 PYs). Only one PWID receiving daily OAT developed reinfection. CONCLUSIONS: Population-level reinfection rates remain elevated after DAA therapy among PWID because of ongoing exposure risk. Engagement of PWID in harm-reduction and support services is needed to prevent reinfections. LAY SUMMARY: Direct-acting antivirals are an effective tool for the treatment of hepatitis C virus, enabling the elimination of the virus. However, some patients who have been successfully treated with direct-acting antivirals are at risk of reinfection. Our findings showed that the risk of reinfection was highest among people with recent injection drug use. Among people who inject drugs, daily use of opioid-agonist therapy was associated with a lower risk of reinfection

Differential spatial distribution of hepatitis B virus by ethnicity in British Columbia, Canada: Expanded role of a large administrative cohort

Introduction Most chronic hepatitis B virus (HBV) infections in Canada are diagnosed among immigrants from endemic countries and lack traditional risk factors while most acute infections are usually diagnosed in Caucasian population with co-occurring risk factors. Thus, understanding geographical distribution of HBV infection by ethnicity could inform screening and care strategies. Objectives and Approach We identified geographic clusters of HBV infection in British Columbia by ethnicity during the years 1990-2015 using the BC Hepatitis Testers Cohort (BC-HTC). The BC-HTC includes ~1.7 million individuals tested for HCV or HIV at the BC Public Health Laboratory or reported as a case of HCV, HIV, or HBV linked to healthcare administrative databases. We plotted maps of HBV diagnoses (acute and chronic) rate at the Dissemination Area level between 1990-2015 stratified by ethnicity and compared this distribution with injection drug use (IDU) distribution in BC. Results The distribution of HBV varied considerably by ethnicity. From 1990 to 2015, a higher rate of HBV infection was found among East Asians and Caucasians followed by South Asians and other ethnicities. East Asians with highest rates were mainly concentrated in Vancouver city, Burnaby and Richmond (Metro Vancouver) while South Asians with highest rates were mostly concentrated in urban areas in Surrey and Abbotsford. Caucasians with higher rates were clustered in Downtown Eastside in Vancouver, Surrey and Abbotsford (Metro Vancouver) and urban areas in Greater Victoria (Vancouver Island), Prince George (Northern BC) and Kamloops (Interior BC). The distribution of IDU closely followed the distribution of HBV among Caucasians but did not align with other ethnic groups. Conclusion/Implications Results highlight distinct areas of HBV infection clustering by ethnicity, which differ from areas with high IDU distribution except in Caucasians. Findings support ethnicity-based HBV screening/prevention and care services to areas with immigrants from HBV-endemic countries and integrated HBV and harm reduction services for early diagnosis and treatment in Caucasians

Effect of metabolic genetic variants on long-term disease comorbidity in patients with type 2 diabetes

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D

PUFA omega-3 and omega-6 biomarkers and sleep : a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE)

Background: n-3 and n-6 PUFAs have physiologic roles in sleep processes. but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters. Objectives: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium. Methods: Harmonized, de novo. individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included alpha-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts. n = 18.791) was categorized as short (= 9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis. Results: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles. the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified. Conclusions: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.Peer reviewe

Effect of metabolic genetic variants on long-term disease comorbidity in patients with type 2 diabetes

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D

Impact of Playground Shade Structures on Ultraviolet Radiation Exposure and Physical Activity among Children at a Childcare Facility

Skin cancer is the most common cancer in Canada, and rates continue to rise. While sunscreen and protective clothing remain critical strategies to reduce skin cancer risk, shade is generally the most effective way to control exposure. There remains a lack of data, particularly in British Columbia (BC), demonstrating the extent to which shade availability reduces ultraviolet radiation (UVR) exposure in a real-world setting and the potential impacts of shade provision on physical activity. We evaluated the impact of shade structures on UVR exposure and physical activity at a Vancouver-area childcare center with an outdoor play area with limited existing shade. 22 children, aged 3–5 years, participated in the study. Three removable shade sails were installed in the outdoor play space, and UVR and physical activity measurements were collected during the spring, summer, and fall months. Ultraviolet B (UVB) radiation data was measured using UVB dosimeters, and physical activity data was measured using accelerometers. Data were collected during each season over a total of four days—two days with shade sails installed and two days with shade sails removed. Overall, with shade installation, UVR exposures and physical activity levels among children were reduced by 50% and 20%, respectively. This study supports the use of shade sails to significantly reduce UVR exposures among preschool-aged children in BC; however, the potential for decreased physical activity from shade sails should be further explored in future research.Medicine, Faculty ofPopulation and Public Health (SPPH), School ofReviewedFacult

Effectiveness of seasonal influenza vaccine in community-dwelling elderly people:a meta-analysis of test-negative design case-control studies

Background The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people. Methods We searched the Cochrane library, Medline, and Embase up to July 13,2014, for test-negative design casecontrol studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions. Findings 35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0.69, 95% CI 0.48-0.99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0-42,95% CI 0.30-0.60; mismatch: OR 0.57,95% CI 0.41-0.79) and widespread (match: 0-54,0.46-0.62; mismatch: OR 0.72,95% CI 0.60-0.85) outbreaks. Interpretation Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population