Robin Ducharme

Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

Objective To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. Design Systematic review and meta-analysis of individual patient data. Data sources Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. Eligibility Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. Results The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. Conclusions Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

Validation of Diagnostic Codes for Intussusception and Quantification of Childhood Intussusception Incidence in Ontario, Canada: A Population-Based Study

OBJECTIVES To validate an algorithm to identify cases of intussusception using the health administrative data of Ontario, Canada, and to apply the algorithm to estimate provincial incidence of intussusception, preceding the introduction of the universal rotavirus vaccination program. STUDY DESIGN We determined the accuracy of various combinations of diagnostic, procedural, and billing codes using the chart-abstracted diagnoses of patients of the Childrens Hospital of Eastern Ontario as the reference standard. We selected an algorithm that maximized positive predictive value while maintaining a high sensitivity and used it to ascertain annual incidence of intussusception for fiscal years 1995-2010. We explored temporal trends in incidence using Poisson regression. RESULTS The selected algorithm included only the International Classification of Diseases (ICD)-9 or ICD-10 code for intussusception in the hospitalization database and was sensitive (89.3%) and highly specific (>99.9%). The positive predictive value of the ICD code was 72.4%, and the negative predictive value was >99.9%. We observed the highest mean incidence (34 per 100000) in male children <1 year of age. Temporal trends in incidence varied by age group. There was a significant mean decrease in incidence of 4% per year in infants (<1 year) until 2004 and rates stabilized thereafter. CONCLUSIONS We have demonstrated that intussusception can be accurately identified within health administrative data using validated algorithms. We have described changes in temporal trends in intussusception incidence in Ontario and established a baseline to allow ongoing monitoring as part of vaccine safety surveillance.

Clinical effects of blood donor characteristics in transfusion recipients: protocol of a framework to study the blood donor–recipient continuum

Introduction When used appropriately, transfusion of red blood cells (RBCs) is a necessary life-saving therapy. However, RBC transfusions have been associated with negative outcomes such as infection and organ damage. Seeking explanations for the beneficial and deleterious effects of RBC transfusions is necessary to ensure the safe and optimal use of this precious resource. This study will create a framework to analyse the influence of blood donor characteristics on recipient outcomes. Methods and analysis We will conduct a multisite, longitudinal cohort study using blood donor data routinely collected by Canadian Blood Services, and recipient data from health administrative databases. Our project will include a thorough validation of primary data, the linkage of various databases into one large longitudinal database, an in-depth epidemiological analysis and a careful interpretation and dissemination of the results to assist the decision-making process of clinicians, researchers and policymakers in transfusion medicine. Our primary donor characteristic will be age of blood donors and our secondary donor characteristics will be donor–recipient blood group compatibility and blood donor sex. Our primary recipient outcome will be a statistically appropriate survival analysis post-RBC transfusion up to a maximum of 8 years. Our secondary recipient outcomes will include 1-year, 2-year and 5-year mortality; hospital and intensive care unit length of stay; rehospitalisation; new cancer and cancer recurrence rate; infection rate; new occurrence of myocardial infarctions and need for haemodialysis. Ethics and dissemination Our results will help determine whether we need to tailor transfusion based on donor characteristics, and perhaps this will improve patient outcome. Our results will be customised to target the different stakeholders involved with blood transfusions and will include presentations, peer-reviewed publications and the use of the dissemination network of blood supply organisations. We obtained approval from the Research Ethics boards and privacy offices of all involved institutions.

Metabolomics of prematurity: analysis of patterns of amino acids, enzymes, and endocrine markers by categories of gestational age

Background:Prematurity may influence the levels of amino acids, enzymes, and endocrine markers obtained through newborn screening. Identifying which analytes are the most affected by degree of prematurity could provide insight into how prematurity impacts metabolism.Methods:Analytes from blood spots assayed by Newborn Screening Ontario between March 2006 and April 2009 were used in this analysis. We examined the associations between the degree of prematurity and the levels of amino acids, enzymes, and endocrine markers in all newborns with and without adjustment for birth weight, feeding status, sample timing, transfusion, and sex.Results:Our analysis included the following cohorts: 373,819 children born at term (>36 wk gestation), 26,483 near-term children (33–36 wk gestation), 4,354 very premature children (28–32 wk gestation), and 1,146 extremely premature children (<28 wk gestation). Of the amino acids showing consistent trends across categories of prematurity, the levels of three amino acids (arginine, leucine, and valine) were at least 50% different between the cohorts of extremely premature and term children. The levels of 17-hydroxyprogesterone increased with increasing prematurity, while thyrotropin-stimulating hormone values consistently decreased with increasing prematurity. None of the three enzyme markers we examined showed a trend in levels across categories of prematurity.Conclusion:This study demonstrates that children at different stages of prematurity are metabolically distinct. Future research should focus on the mechanism by which specific analytes are influenced by prematurity.

Vaccination attitudes and mobile readiness: A survey of expectant and new mothers

Sub-optimal vaccination coverage and recent outbreaks of vaccine-preventable diseases serve as a reminder that vaccine hesitancy remains a concern. ImmunizeCA, a new smartphone app to help track immunizations, may address several reasons for not vaccinating. We conducted a study to describe demographic variables, attitudes, beliefs and information sources regarding pediatric vaccination in a sample of childbearing women who were willing to download an immunization app. We also sought to measure their current mobile usage behaviors and determine if there is an association between participant demographics, attitudes, beliefs and information sources regarding pediatric vaccination and mobile usage. We recruited participants using a combination of passive and active methods at a tertiary care hospital in Ottawa, Canada. We used surveys to collect demographic information, examine attitudes, behavior, and information sources regarding immunization and self-reported mobile phone usage. A total of 54 women participated. The majority had positive attitudes toward vaccination (96%) and intended to vaccinate their children (98%). Participants were interested in information on pediatric vaccination (94%), and found information from public health the most reliable and accessible (78%). Participants also trusted immunization information from their doctor or nurse and public health (83%) more than other sources. There was variability in participant use of mobile apps for other purposes. The median participant mobile readiness score was 3.2. We found no significant associations between participant age, behavior and attitudes regarding vaccination and mobile readiness scores. This is the first evaluation of mobile readiness for a smartphone app to track immunizations. Our findings suggest that there exists an opportunity to provide reliable information on vaccination through mobile devices to better inform the public, however predictors of individual engagement with these technologies merits further study.

Accurate prediction of gestational age using newborn screening analyte data

BACKGROUND Identification of preterm births and accurate estimates of gestational age for newborn infants is vital to guide care. Unfortunately, in developing countries, it can be challenging to obtain estimates of gestational age. Routinely collected newborn infant screening metabolic analytes vary by gestational age and may be useful to estimate gestational age. OBJECTIVE We sought to develop an algorithm that could estimate gestational age at birth that is based on the analytes that are obtained from newborn infant screening. STUDY DESIGN We conducted a population-based cross-sectional study of all live births in the province of Ontario that included 249,700 infants who were born between April 2007 and March 2009 and who underwent newborn infant screening. We used multivariable linear and logistic regression analyses to build a model to predict gestational age using newborn infant screening metabolite measurements and readily available physical characteristics data (birthweight and sex). RESULTS The final model of our metabolic gestational dating algorithm had an average deviation between observed and expected gestational age of approximately 1 week, which suggests excellent predictive ability (adjusted R-square of 0.65; root mean square error, 1.06 weeks). Two-thirds of the gestational ages that were predicted by our model were accurate within ±1 week of the actual gestational age. Our logistic regression model was able to discriminate extremely well between term and increasingly premature categories of infants (c-statistic, >0.99). CONCLUSION Metabolic gestational dating is accurate for the prediction of gestational age and could have value in low resource settings.

Association between socioeconomic status and adverse events following immunization at 2, 4, 6 and 12 months

Using a population-based self-controlled case series design, we examined data on children born between the years 2002 and 2009 in the province of Ontario, Canada. We specifically examined how socioeconomic status (SES) influences rates of adverse events following immunization (AEFI), defined as emergency room visits and / or hospital admissions. For vaccination at 2, 4 and 6 mo combined, the relative incidence of AEFI (95% CI) in the first 72 h after vaccination was 0.69 (0.67 to 0.71). For all three vaccinations combined, we observed no relationship between the relative incidence of an event and quintile of socioeconomic status (p = 0.1433). For the 12-mo vaccination alone, the relative incidence of events (95% CI) on days 4 to 12 following immunization was 1.35 (1.31 to 1.38). We observed a significant relationship between socioeconomic status and vaccination at 12 mo, with lower SES being associated with a higher relative incidence of events (p = 0.0075). When the lowest 2 quintiles of income combined were compared with the highest 3 quintiles, the relative incidence ratio (95% CI) was 0.94 (0.89 to 0.99, p = 0.02). These results translate to 150 additional adverse events in the lower SES quintiles as compared with the higher SES quintiles for every 100,000 children vaccinated, or 1 additional event for every 666 individuals vaccinated. Future studies should explore potential explanations for this observation.

Increased emergency room visits or hospital admissions in females after 12-month MMR vaccination, but no difference after vaccinations given at a younger age

BACKGROUND Previous studies have suggested that a childs sex may be a predictor of vaccine reactions. METHODS We used a self-controlled case series design, an extension of retrospective cohort methodology which controls for fixed confounders using a conditional Poisson modeling approach. We compared a risk period immediately following vaccination to a control period farther removed from vaccination in each child and estimated the relative incidence of emergency room visits and/or hospital admissions following the 2-, 4-, 6-, and 12-month vaccinations to investigate the effect of sex on relative incidence. All infants born in Ontario, Canada between April 1, 2002 and March 31, 2009 were eligible for study inclusion. RESULTS In analyses combining immunizations at 2, 4 and 6 months and examining these vaccinations separately, there was no significant relationship between the relative incidence of an event and sex of the child. At 12 months, we observed a significant effect of sex, with female sex being associated with a significantly higher relative incidence of events (P=0.0027). The relative incidence ratio (95% CI) comparing females to males following the 12-month vaccination was 1.08 (1.03 to 1.14), which translates to 192 excess events per 100,000 females vaccinated compared to the number of events that would have occurred in 100,000 males vaccinated. CONCLUSIONS As the MMR vaccine is given at 12 months of age in Ontario, our findings suggest that girls may have an increased reactogenicity to the MMR vaccine which may be indicative of general sex differences in the responses to the measles virus.

Association between Birth Order and Emergency Room Visits and Acute Hospital Admissions following Pediatric Vaccination: A Self-Controlled Study

Objective We investigated the association between a childs 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.

The use of relative incidence ratios in self-controlled case series studies: an overview

BackgroundThe self-controlled case series (SCCS) is a useful design for investigating associations between outcomes and transient exposures. The SCCS design controls for all fixed covariates, but effect modification can still occur. This can be evaluated by including interaction terms in the model which, when exponentiated, can be interpreted as a relative incidence ratio (RIR): the change in relative incidence (RI) for a unit change in an effect modifier.MethodsWe conducted a scoping review to investigate the use of RIRs in published primary SCCS studies, and conducted a case-study in one of our own primary SCCS studies to illustrate the use of RIRs within an SCCS analysis to investigate subgroup effects in the context of comparing whole cell (wcp) and acellular (acp) pertussis vaccines. Using this case study, we also illustrated the potential utility of RIRs in addressing the healthy vaccinee effect (HVE) in vaccine safety surveillance studies.ResultsOur scoping review identified 122 primary studies reporting an SCCS analysis. Of these, 24 described the use of interaction terms to test for effect modification. 21 of 24 studies reported stratum specific RIs, 22 of 24 reported the p-value for interaction, and less than half (10 of 24) reported the estimate of the interaction term/RIR, the stratum specific RIs and interaction p-values. Our case-study demonstrated that there was a nearly two-fold greater RI of ER visits and admissions following wcp vaccination relative to acp vaccination (RIR = 1.82, 95 % CI 1.64–2.01), where RI estimates in each subgroup were clearly impacted by a strong healthy vaccinee effect.ConclusionsWe demonstrated in our scoping review that calculating RIRs is not a widely utilized strategy. We showed that calculating RIRs across time periods is useful for the detection of relative changes in adverse event rates that might otherwise be missed due to the HVE. Many published studies of vaccine-associated adverse events could have missed/underestimated important safety signals masked by the HVE. With further development, our application of RIRs could be an important tool to address the HVE, particularly in the context of self-controlled study designs.