Upper respiratory tract infections (URTI) are the most common infectious disease for children in North America and account for a large portion of health-service utilization (HSU)( Reference Heikkinen and Järvinen 1 ). Pre-school children experience six to eight URTI per year( Reference Griffiths, Goldring and Griffiths 2 ), with approximately 50 % seeking medical attention in the outpatient or emergency department setting and roughly 1 % requiring hospitalization( Reference Carabin, Gyorkos and Soto 3 – Reference Haskins 6 ). A number of studies have suggested that low vitamin D levels may play a role in susceptibility to URTI in children. Suggested mechanisms have included improved immune and inflammatory response through T-helper cell regulation, immunoglobulin production and stimulation of the antimicrobial peptide cathelicidin( Reference Gombart, Borregaard and Koeffler 7 – Reference Hewison 9 ). Two meta-analyses, including randomized controlled trials with both children and adults, found that vitamin D had a protective effect against respiratory tract infections (OR=0·64; 95 % CI 0·49, 0·84( Reference Bergman, Lindh and Bjorkhem-Bergman 10 ) and OR=0·582; 95 % CI 0·417, 0·812( Reference Charan, Goyal and Saxena 11 )). However, a meta-analysis of randomized controlled trials involving only children found no association between vitamin D and risk of acute respiratory infections (relative risk (RR)=0·79, 95 % CI 0·55, 1·13)( Reference Xiao, Xing and Yang 12 ).
Given the existing literature supporting a relationship between vitamin D and URTI risk, we hypothesized that children’s serum 25-hydroxyvitiamin D concentration and vitamin D supplement use would be negatively associated with HSU for URTI. To our knowledge, no study has yet evaluated vitamin D status and HSU for URTI in a prospective cohort of healthy young children. Thus the primary objective of the present study was to determine whether serum 25-hydroxyvitamin concentration in early childhood was associated with HSU for URTI including: (i) any hospital admission (HA), emergency department visit (ED) and outpatient sick visit (SV; i.e. Total HSU); (ii) HA; (iii) ED; and (iv) SV. The secondary objectives were to determine whether oral vitamin D supplementation in pregnancy or childhood was associated with Total HSU, HA, ED or SV for URTI.
Methods
A cohort of healthy urban children, 0 to 5 years of age, who participated in the TARGet Kids! (The Applied Research Group for Kids) practice-based research network between December 2008 and March 2013, were included in the present study. Participants were recruited from seven large paediatric or family medicine group practices in Toronto, Canada (latitude 43·4°N). Children were excluded if they had conditions affecting growth, chronic condition(s) except for asthma, or severe developmental delay( Reference Carsley, Borkhoff and Maguire 13 ). A detailed questionnaire, adapted from the Canadian Community Health Survey, was completed by the parent or guardian of each child at the time of enrolment to collect data on participant characteristics and demographics( 14 ).
Measurements
Exposure definitions
The primary exposure was serum 25-hydroxyvitamin D as a continuous variable in nmol/l. Total 25-hydroxyvitamin D was measured from blood serum collected during a well-child visit (between December 2008 and March 2013) using a competitive two-step chemiluminescence assay (LIAISON 25 OH Vitamin D TOTAL Assay; DiaSorin SpA, Vercelli, Italy)( 15 ) at the Mount Sinai Services Laboratory (Toronto, ON, Canada). Intra-assay imprecision of the assay was 7·2 % at a concentration of 213 nmol/l and inter-assay imprecision was 4·9 % at 32 nmol/l, 8·9 % at 77 nmol/l and 17·4 % at 213 nmol/l. These values are well within acceptable limits for biochemical measurements( Reference Maunsell, Wright and Rainbow 16 , Reference Singh, Taylor and Reddy 17 ). 25-Hydroxyvitamin D concentration was measured continuously as well as dichotomized at <50 and <75 nmol/l, respectively, based on the American Academy of Pediatrics/Institute of Medicine and Canadian Paediatric Society reference cut-off points( 18 – Reference Armstrong 20 ).
The secondary exposures, measured at the same visit or the first TARGet Kids! visit (if laboratory data were unavailable), were:
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1. Single-nutrient oral vitamin D prenatal supplementation measured by parental report using the question: ‘Did your child’s biological mother take any vitamins or supplements during her pregnancy?’ This captured supplementation during the entire pregnancy and was not broken down by trimester. We only included single-nutrient vitamin D supplements in order to differentiate from those women taking a prenatal multivitamin (approximately 90 % of women were taking a prenatal multivitamin).
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2. Oral vitamin D supplementation in childhood measured by parental report using the following questions: ‘Does your child take a vitamin D-containing supplement regularly?’ and ‘In a typical day, how much does your child take?’ We combined the dose of vitamin D in international units (IU) from multivitamins and single-nutrient vitamin D supplements to estimate current total daily intake of supplemental vitamin D.
Outcome definitions
All residents of Ontario are insured through the Ontario Health Insurance Plan (OHIP), a universal single-payer health-care system, and are provided a unique health insurance number (OHIP number). For the current study, prospectively collected data from the TARGet Kids! practice-based research network were linked to three health administrative databases at the individual level using the encrypted OHIP number, with 98 % success. This type of linkage allowed for protection of the participants’ identities while examining their HSU across different databases. Linkage occurred at the Institute for Clinical Evaluative Sciences in Ontario, Canada, which is a prescribed registry under Ontario’s Personal Health Information Protection Act and permits the collection of health-service data without patient consent. The health administrative databases used were:
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1. the Canadian Institute for Health Information’s discharge abstract database (DAD) to obtain data on HA;
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2. the Canadian Institute for Health Information’s National Ambulatory Care Reporting System (NACRS) to obtain data on ED; and
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3. the OHIP physician claims database to obtain information on fee-for-service physician billings for SV.
The observation window for the outcomes included HSU visits that occurred 365 d before and after the exposure measurements (1 year before and after the date that 25-hydroxyvitamin D was measured for the primary analysis; and 1 year before and after the date that vitamin D supplement data were captured for the secondary analyses).
The International Classification of Diseases, 10th revision (ICD-10) defines URTI as a disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx or trachea)( 21 ). The ICD-10 diagnostic codes were used to identify HSU for URTI in the DAD (HA) and NACRS (ED) databases. The most responsible diagnosis was used and has been shown to have the highest predictive accuracy( Reference Juurlink, Preyra and Croxford 22 ). OHIP fee-for-service physician diagnostic codes were used to define a URTI for SV. See the online supplementary material for included URTI diagnostic codes. In order to calculate Total HSU, HA+ED+SV were combined.
HSU before 28 d of life was excluded to avoid complications from birth. Health-service episodes less than 2 weeks apart were considered a single event to avoid counting multiple visits for the same URTI. Priority was given to HA, then ED and then SV.
Other variables
Covariates that might influence the relationship between 25-hydroxyvitamin D and HSU were identified a priori through a literature review and measured at the time of laboratory analysis or first TARGet Kids! visit (if laboratory data were unavailable). These included age( Reference Newacheck 23 , Reference Wayse, Yousafzai and Mogale 24 ), sex( Reference Falagas, Mourtzoukou and Vardakas 25 ), number of children in the household( Reference Koopman, Smit and Heijnen 26 ), day care/pre-school attendance( Reference Koopman, Smit and Heijnen 26 – Reference Ball, Holberg and Albous 28 ) and BMI Z-score( Reference Campitelli, Rosella and Kwong 29 ).
Weight was measured using a precision digital scale and height was measured using a length board for children under 2 years and a stadiometer (SECA) for children over 2 years. BMI was calculated as weight in kilograms divided by the square of height in metres (kg/m2)( Reference Pietrobelli, Faith and Allison 30 ). BMI Z-scores were calculated using the WHO growth standards( 31 ).
Statistical analysis
The total numbers of HA, ED and SV for URTI were described as counts. For the primary analysis, multivariable quasi Poisson regression was used to account for overdispersion of the data. The associations between 25-hydroxyvitamin D and (i) Total HSU, (ii) HA, (iii) ED and (iv) SV for URTI were tested. An offset was used to account for variation in the window of observation. The models were adjusted by the covariates specified above regardless of statistical significance to avoid bias that can result from standard variable selection techniques( Reference Harrell 32 , Reference Little and Rubin 33 ). Sensitivity analyses were performed repeating the primary analysis but including only children with 25-hydroxyvitamin D levels below <50 and <75 nmol/l based on the Academy of Pediatrics/Institute of Medicine and Canadian Paediatric Society reference cut-off points, respectively, to evaluate consistency of findings( 18 – Reference Armstrong 20 ).
We assessed for multicollinearity for all covariates using the variance inflation factor( Reference O’Brien 34 ). All variance inflation factors were <5, so we concluded that multicollinearity was unlikely to be a problem in the current analysis( Reference O’Brien 34 ).
Circulating 25-hydroxyvitamin D concentration varied from season to season, with higher levels during the summer and lower levels during the winter. To account for variability in the date of blood sampling, we adjusted the exposure (25-hydroxyvitamin D) for seasonal variability using the sine curve method described by Zhang et al.( Reference Zhang, Ahn and Yu 35 ). This allowed us to adjust for seasonal variation in vitamin D. Considering HSU was measured in all seasons over a 2-year period and 25-hydroxyvitamin D was seasonally adjusted, season is unlikely to be a potential confounder and was not included as a covariate.
Non-linearity was explored through graphical presentation of the data and spline analysis using three knots. A likelihood ratio test was conducted between the linear and non-linear models (nested models) to compare the goodness-of-fit. A P value of 0·96 meant we did not reject the linear model.
Multiple imputations were performed, using transcan in the R package Hmisc, on covariates (number of children in the household, day care/pre-school attendance and BMI Z-score) in order to overcome bias that can result from missing data( Reference Little and Rubin 33 ). No variables had more than 5 % missing data. We did not impute missing data for the exposures or the outcomes.
For the secondary analyses, the above multivariable quasi Poisson regression models were repeated but with vitamin D supplementation in pregnancy and childhood as the exposure variables with the same covariates and HSU outcomes.
All P values were two-tailed and P<0·05 was considered statistically significant. All statistical analyses were conducted with the statistical software packages SAS version 9.3 and R version 3.3.
Results
Of the 4962 children who met the inclusion criteria and provided consent to participate, 2926 had 25-hydroxyvitamin D measured and were included in the primary analysis (see Fig. 1). In the secondary analyses which evaluated maternal vitamin D supplementation and child vitamin D supplementation, 4672 and 4132 children were included, respectively. Baseline characteristics of children with and without laboratory testing are outlined in Table 1. Children with laboratory testing were slightly older and were more likely to take a vitamin D-containing supplement; otherwise there was no clinically meaningful difference between the two groups. Fifty-two per cent of the participants were male and mean 25-hydroxyvitamin D was 84 (sd 29·7) nmol/l (range 11–355 nmol/l). 25-Hydroxyvitamin D levels below 50 and 75 nmol/l were found in 218 and 1267 children, respectively. Ten per cent of mothers took a single-nutrient vitamin D supplement during pregnancy. Forty-seven per cent of children were regularly consuming a vitamin D-containing supplement (mean dose was 4·9 (sd 6·9) µg/d (196 (sd 276) IU/d)).
Selection of participants for the present study
Sociodemographic characteristics of the TARGet Kids! cohort, Toronto Canada, 2008–2013
URTI, upper respiratory tract infection; ID, identification number.
* 110/517 (21 %) of all hospital admissions were related to URTI (429 with unique ID).
† 929/3954 (23 %) of all emergency department visits were related to URTI (2189 with unique ID).
‡ 7577/39 429 (19 %) of all outpatient sick visits were related to URTI (4940 with unique ID).
During the observation period, 4896 (97 %) children had at least one HSU of which 19 % were for URTI, 431 (9 %) children had at least one HA of which 21 % were for URTI, 2191 (44 %) children had at least one ED of which 23 % were for URTI, and 4883 (about 98 %) children had at least one SV of which 19 % were for URTI.
For the primary analysis, we evaluated whether serum 25-hydroxyvitamin D concentration was associated with HSU for URTI. No statistically significant association was found in the unadjusted or adjusted models between 25-hydroxyvitamin D (in 10 nmol/l increments) and Total HSU (adjusted RR (aRR)=1·01; 95 % CI 0·99, 1·02; see Fig. 2), HA (aRR=1·01; 95 % CI 0·92, 1·10), ED (aRR=0·99; 95 % CI 0·96, 1·02) or SV (aRR=1·01; 95 % CI 1·00, 1·02; see Tables 2 and 3).
Unadjusted relative risk (RR) of 25-hydroxyvitamin D concentration (in 10 nmol/l increments) and total health-service utilization for upper respiratory tract infections in a 2-year period in the TARGet Kids! cohort, Toronto, Canada, 2008–2013. ——— represents the line of best fit for the data and the grey area represents the 95 % CI
Multivariate unadjusted and adjustedFootnote * relative risk of health-service utilization (HSU) for upper respiratory tract infection (URTI) in relation to serum 25-hydroxyvitamin D and vitamin D supplementation, TARGet Kids! cohort, Toronto, Canada, 2008–2013
RR, relative risk; aRR, adjusted relative risk.
* Adjusted for age, sex, BMI Z-score, number of children in the household and day care/pre-school attendance.
† Any HSU for URTI (HA+ED+SV).
‡ Risk of one hospital admission, one emergency department visit or one outpatient sick visit for URTI.
§ Serum 25-hydroxyvitamin D in 10 nmol/l increments.
Quasi Poisson regression model for adjusted association between 25-hydroxyvitamin D and health-service utilization (HSU) for upper respiratory tract infection (URTI), TARGet Kids! cohort, Toronto, Canada, 2008–13
aRR, adjusted relative risk; ref., reference category.
* A 0·5 unit increase in BMI Z-score was associated with a 4 % increased incidence rate of Total HSU for URTI, 9 % increased incidence rate of ED for URTI and 3 % increased incidence rate of SV for URTI.
† Children aged >4 years had a 38 % lower risk of incidence rate of Total HSU for URTI compared with children aged <2 years.
‡ Children aged 2–4 years had a 20 % lower risk of incidence rate of Total HSU for URTI compared with children aged <2 years.
§ Attending day care was associated with a 20 % increased incidence rate of Total HSU for URTI compared with children who did not attend day care.
In the sensitivity analysis, no statistically significant association was found in the unadjusted or adjusted models between 25-hydroxyvitamin D (in 10 nmol/l increments) and Total HSU among children with 25-hydroxyvitamin D levels <50 nmol/l (aRR=0·94; 95 % CI 0·81, 1·09) and <75 nmol/l (aRR=0·98; 95 % CI 0·93, 1·03).
Further, no statistically significant associations were identified between prenatal vitamin D supplementation and Total HSU, HA, ED or SV (see Table 2). Similarly, no statistically significant associations were found between child vitamin D supplementation (in 2·5 µg/d (100 IU/d) increments) and Total HSU, HA, ED or SV (see Table 2).
Discussion
We conducted a cohort study to evaluate the relationship between children’s 25-hydroxyvitamin D concentration, prenatal and child vitamin D supplement use and HSU for URTI. Given that URTI in young children is the most common reason for seeking health care, understanding this relationship could result in important preventive benefits. The reasons for HA, ED visits and SV in the present study were similar to those in other North American studies( Reference To, Guttmann and Dick 36 ), but we did not find clinically meaningful associations between children’s serum vitamin D level, prenatal or child vitamin D supplementation and HSU for URTI. To our knowledge no study has yet evaluated vitamin D status and HSU for URTI in a cohort of healthy young children.
Other studies which have evaluated the association between vitamin D status and URTI have produced mixed results( Reference Bergman, Lindh and Bjorkhem-Bergman 10 – Reference Xiao, Xing and Yang 12 ). Two meta-analyses of randomized controlled trials including both adults and children found that vitamin D had a protective effect against respiratory tract infections( Reference Bergman, Lindh and Bjorkhem-Bergman 10 , Reference Charan, Goyal and Saxena 11 ). Another meta-analysis that focused on randomized controlled trials in children found no association between 25-hydroxyvitamin D and risk of acute respiratory infections( Reference Xiao, Xing and Yang 12 ).
Two randomized controlled trials have assessed HSU following vitamin D supplementation in pregnancy. Griffiths et al. found no evidence that prenatal vitamin D supplementation (placebo, 20 µg/d (800 IU/d) or a single bolus of 5000 µg (200 000 IU)) from 27 weeks to delivery influenced overall HSU in children from in London, England in the first 3 years( Reference Griffiths, Goldring and Griffiths 2 ). They also found no association between 25-hydroxyvitamin D concentrations in the children at age 3 years (n 65) and HSU. However, their study was limited by small sample size and only a small number of subjects had adequate (>50 nmol/l) vitamin D status at delivery( 18 ). In Auckland, New Zealand, Grant et al. found an association between vitamin D supplementation during the last trimester of pregnancy and the first 6 months of infancy (placebo/placebo, 40/10 µg/d (1000/400 IU/d) or 80/20 µg/d (2000/800 IU/d)) among 260 mother–child dyads and reduced primary-care visits for acute respiratory infections from 6 to 18 months (P=0·048) for higher-dose vitamin D v. placebo( Reference Grant, Kaur and Waymouth 37 , Reference Grant, Stewart and Scragg 38 ). However, they had HSU data only up to 18 months and combined data from different sources to determine the outcome, including parent report up to 6 months of age, hospitalization data up to 12 months and primary-care visit data up to 18 months of age( Reference Grant, Kaur and Waymouth 37 ). In comparison, the current study had HSU outcome data over a 2-year period from three databases including information on HA, ED and SV (1 year before and 1 year after the exposures were measured). Also, the mean 25-hydroxyvitamin D concentration at 18 months in Grant et al.’s paper was 63, 61 and 59 nmol/l in the placebo, low- and high-dose arms, respectively (n221)( Reference Grant, Kaur and Waymouth 37 ), and these are lower than the mean 25-hydroxyvitmain D level in the current study (84 nmol/l, n 2926).
Strengths of the current study included: a relatively large sample size of healthy young children, with nearly 3000 serum 25-hydroxyvitmain D measurements; HSU data on all participants with sufficient power to detect a small association; detailed questionnaire data on vitamin D supplementation; as well as data on numerous potential confounders( Reference Roos, Menec and Currie 39 , Reference Doiron, Raina and Fortier 40 ). Further, the study was able to link clinical data from a large cohort study and health administrative data from a publicly funded health-care system.
Limitations of the present study include its observational nature, thus causality cannot be inferred. Second, health administrative data were not collected for the purposes of doing research and thus the accuracy of physician billings may have led to misclassification of the outcome. However, the use of the most responsible diagnosis has been shown to have the highest predictive accuracy and lowest likelihood of misclassification( Reference Juurlink, Preyra and Croxford 22 ). Third, we were unable to measure the dose of or adherence to vitamin D supplements taken during pregnancy and thus we were unable to determine whether a dose–relationship exists between prenatal supplementation and HSU. Forth, OHIP fee-for-service physician billing data for outpatient sick visits are limited to one diagnosis per encounter and this may have resulted in missed outcomes. Finally, the mean 25-hydroxyvitamin D concentration in the present population was 84 nmol/l (range 11–355 nmol/l), which is similar to other national studies, but may not have been sufficiently low to demonstrate an association( Reference Langlois, Greene-Finestone and Little 41 , Reference El Hayek, Pham and Finch 42 ). However, in a sensitivity analysis, we did not identify an association with HSU in the population of children (n 218) with 25-hydroxyvitamin D concentration below 50 nmol/l.
The results from the current study do not support the hypothesis that children’s serum 25-hydroxyvitiamin D concentration or vitamin D supplement use (both during pregnancy and childhood) is negatively associated with HSU for URTI, with parameter estimates near null and relatively tight confidence limits. Studies in children with higher risk of low 25-hydroxyvitamin D concentrations or combined mother/infant supplementation may be necessary to demonstrate an impact on HSU for URTI.
Conclusion
While vitamin D may be a potential preventive intervention for URTI, in the present study we found no evidence to support an association between vitamin D status (continuously and dichotomized at <50 and <75 nmol/l), vitamin D supplementation in pregnancy or childhood and HSU for URTI in children. However, most of the participants in the study had adequate vitamin D status.
Acknowledgements
Acknowledgments: The authors thank all of the participating families for their time and involvement in TARGet Kids! and are grateful to all practitioners who are currently involved in the TARGet Kids! practice-based research network. Financial support: This work was supported by The Ontario Lung Association, Ontario Thoracic Society grant-in-aid programme. Funding to support TARGet Kids! was provided by multiple sources including the Canadian Institutes for Health Research (CIHR), namely the Institute of Human Development, Child and Youth Health and the Institute of Nutrition, Metabolism and Diabetes, as well as the St. Michael’s Hospital Foundation. Funding to support J.A.O. was provided by the CIHR doctoral award at St. Michael’s Hospital and the Clinician Scientist Training Program (CSTP) at the Hospital for Sick Children. Funding agencies had no role in the design, collection, analyses or interpretation of the results of this study or in the preparation, review or approval of the manuscript. This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors, and not necessarily those of CIHI. Conflict of interest: The authors have no conflicts of interest or financial relationships relevant to this article to disclose. Authorship: J.A.O. and J.L.M. designed the research study. T.T., D.L.O., P.C.P. and C.S.B. helped to refine the study design. J.A.O., J.L.M. and K.E.T. analysed the data. All authors contributed to the interpretation of results. J.A.O. and J.L.M. drafted the manuscript. All authors read and approved the final manuscript. J.A.O. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ethics of human subject participation: This study was approved by the Hospital for Sick Children Research Ethics Board and Institute for Clinical Evaluative Sciences (ICES). All TARGet Kids! participating parents provided consent for their child’s data to be linked with health administrative data.
TARGet Kids! Collaboration. Co-Leads: Catherine S. Birken, Jonathon L. Maguire. Scientific Committee: Kawsari Abdullah, Yamna Ali, Laura N. Anderson, Imaan Bayoumi, Cornelia M. Borkhoff, Sarah Carsley, Shiyi Chen, Yang Chen, Denise Darmawikarta, Cindy-Lee Dennis, Karen Eny, Stephanie Erdle, Kayla Furlong, Kanthi Kavikondala, Christine Koroshegyi, Christine Kowal, Grace Jieun Lee, Dalah Mason, Jessica Omand, Patricia C. Parkin, Navindra Persaud, Lesley Plumptre, Meta van den Heuvel, Shelley Vanderhout, Peter Wong, Weeda Zabih. Site Investigators: Murtala Abdurrahman, Barbara Anderson, Kelly Anderson, Gordon Arbess, Jillian Baker, Tony Barozzino, Sylvie Bergeron, Dimple Bhagat, Nicholas Blanchette, Gary Bloch, Joey Bonifacio, Ashna Bowry, Anne Brown, Jennifer Bugera, Douglas Campbell, Sohail Cheema, Elaine Cheng, Brian Chisamore, Ellen Culbert, Karoon Danayan, Paul Das, Mary Beth Derocher, Anh Do, Michael Dorey, Kathleen Doukas, Anne Egger, Allison Farber, Amy Freedman, Sloane Freeman, Keewai Fung, Sharon Gazeley, Charlie Guiang, Dan Ha, Curtis Handford, Laura Hanson, Hailey Hatch, Teresa Hughes, Sheila Jacobson, Lukasz Jagiello, Gwen Jansz, Paul Kadar, Tara Kiran, Lauren Kitney, Holly Knowles, Bruce Kwok, Sheila Lakhoo, Margarita Lam-Antoniades, Eddy Lau, Fok-Han Leung, Alan Li, Jennifer Loo, Joanne Louis, Sarah Mahmoud, Roy Male, Vashti Mascoll, Rosemary Moodie, Julia Morinis, Maya Nader, Sharon Naymark, Patricia Neelands, James Owen, Jane Parry, Michael Peer, Kifi Pena, Marty Perlmutar, Navindra Persaud, Andrew Pinto, Tracy Pitt, Michelle Porepa, Vikky Qi, Nasreen Ramji, Noor Ramji, Jesleen Rana, Alana Rosenthal, Katherine Rouleau, Janet Saunderson, Rahul Saxena, Vanna Schiralli, Michael Sgro, Hafiz Shuja, Susan Shepherd, Hafiz Shuja, Barbara Smiltnieks, Cinntha Srikanthan, Carolyn Taylor, Suzanne Turner, Fatima Uddin, Joanne Vaughan, Thea Weisdorf, Sheila Wijayasinghe, Peter Wong, Anne Wormsbecker, Ethel Ying, Elizabeth Young, Michael Zajdman, Ian Zenlea. Advisory Committee: Eddy Lau, Andreas Laupacis, Patricia C. Parkin, Michael Salter, Peter Szatmari, Shannon Weir. Research Team: Charmaine Camacho, Arthana Chandraraj, Dharma Dalwadi, Ayesha Islam, Thivia Jegathesan, Tarandeep Malhi, Megan Smith, Laurie Thompson. Applied Health Research Centre: Christopher Allen, Bryan Boodhoo, Judith Hall, Peter Juni, Gerald Lebovic, Karen Pope, Jodi Shim, Kevin Thorpe. Mount Sinai Services Laboratory: Azar Azad.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/S1368980017000921
