Optimizing Early Child Development in the Primary Care Practice Setting: Pragmatic Randomized Trial of Iron Treatment for Young Children With Non-anemic Iron Deficiency (OptEC)
Phase: NA
Conditions: Non-anemic Iron Deficiency
Sponsor: The Hospital for Sick Children

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
1 
 
 
NCT01481766

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
2 
LIST OF INVESTIGATORS 
 
Principal/Qualified Investigator: 
 
Dr Patricia Parkin, Hospital for Sick Children, Toronto, Ontario 
 
 
 
Co-Investigators:  
Dr Catherine Birken, Hospital for Sick Children, Toronto, Ontario  
 
Dr Darcy Fehlings, Holland Bloorview Kids Rehabilitation Hospital, Toronto, Ontario 
  
Dr Jonathon Maguire, St. Michael’s Hospital, Toronto, Ontario  
Dr Muhammad Mamdani, St. Michael’s Hospital, Toronto, Ontario 
        
Dr Eva Mamak, Hospital for Sick Children, Toronto, Ontario 
Dr Colin Macarthur, Hospital for Sick Children, Toronto, Ontario   
 
 
 
 
  
Kevin Thorpe, St. Michael’s Hospital, Toronto, Ontario   
 
 
 
Dr Stanley Zlotkin, Hospital for Sick Children, Toronto, Ontario 
Dr. Kawsari Abdullah, Hospital for Sick Children, Toronto, Ontario 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
3 
BACKGROUND: 
 
PREVENTIVE CARE AND SCREENING DURING WELL-CHILD VISITS IN 
PEDIATRIC PRIMARY CARE PRACTICE  
Providing preventive services during well-child visits is a defining component of 
pediatric primary care practice.1  Physicians are amongst the only professionals who see nearly 
all preschool children, and thus they are in a unique position to provide this care; however, a 
recent US study evaluating the quality of ambulatory care delivered to children showed that 
children received only 40.7% of indicated preventive care, according to 57 quality indicators.2  It 
has been proposed that failure to deliver preventive services could be more detrimental to 
children than any other age group given the potential for early investments to establish optimal 
trajectories for health and well-being.3  There have been recent calls to ‘rethink’ pediatric 
primary care with an emphasis on the development of scientific evidence.4,5  Given the limited 
time allowed for each physician-patient encounter, priority should be placed on those topics both 
clinically important and uniquely responsive to the personal intervention of the physician.5  A 
recent survey asked US pediatric primary care providers to identify important yet inadequately 
addressed research questions; these included understanding the effectiveness of services 
provided as part of well-child care.6 
 
There are critical gaps in scientific evidence regarding the effectiveness of screening in 
pediatric practice.  A recent study of 42 well-child care preventive interventions recommended 
by major organizations identified 21 screening recommendations for which there are significant 
gaps in evidence, leading the authors to consider this a “challenge to our profession”.7   High 
quality evidence is often based on the results of randomized controlled trials, and our research 
group has identified a paucity of randomized controlled trials (RCTs) in the field of pediatric 
medicine.  Over the 20 year period 1985-2005 in leading general medical journals, pediatric 
RCTs increased by only 0.4 RCTs/year, in contrast to adult RCTs which increased by almost 5 
RCTs/year; 8 in the same time period in leading specialty journals, pediatric RCTs increased by 
only 17 RCTs/year, in contrast to adult RCTs which increased by 90 RCTs/year.9  These findings 
have lead the editor of a leading pediatric journal to conclude that “We believe that the data 
presented by Cohen et al should be a wake-up call to pediatric investigators, department chairs, 
and research center directors. Advancement of the health of children and adolescents requires 
sophisticated, high-quality research in which RCTs are a keystone.10 
 
High quality child health research, including high quality randomized controlled trials, is 
urgently needed.  However, there are methodological challenges.  Moyer and Butler have 
identified that “The time scale is long for many important outcomes; many conditions of interest 
are adult diseases with behavioral precursors in childhood”.7 Given this challenge, there are 
meaningful child health outcomes that can be measured in shorter time periods.   
 
We believe that interventions which optimize early child development should be given 
high priority in child health research.  Further, we believe that there is an urgent need to examine 
the role of laboratory screening of young children for iron deficiency, followed by evaluating the 
effectiveness of treatment for those identified with iron deficiency, as three decades of research 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
4 
suggests that this may be an unrealized and unique opportunity to prevent poor developmental 
outcomes in children. 
 
The over-arching aim of this new research collaboration is to optimize early childhood 
development in the primary care physician practice setting.  The focus will be on advancing the 
evidence base for a screening intervention aimed at improving early childhood development.  
Specifically, we will determine the effectiveness of laboratory screening for iron deficiency 
followed by oral iron treatment to improve developmental outcomes.  This aim has been selected 
because the question is highly relevant to child health, is pragmatic and responsive to physician 
care in primary care practice settings, and is feasible and efficient to study within our newly 
developed practice based research platform called TARGet Kids!. 
 
EARLY CHILD DEVELOPMENT AND IRON DEFICIENCY 
Prevalence of Iron Deficiency and Iron Deficiency Anemia – Nationally representative data 
from the US indicates a peak prevalence in children 1-3 years of age 9% and 3%, for iron 
deficiency and iron deficiency anemia respectively.11,12  Although there are no similar nationally 
representative data for Canadian children, regional studies suggest similar rates,13-22 leading 
experts to conclude that “iron deficiency is an inadequately addressed and significant public 
health problem among Canadian infants and children”.23 
 
Opportunities for Early Detection – The state of non-anemic iron deficiency (NAID) is the 
latent period which, if left untreated, may lead to symptomatic iron deficiency anemia (IDA).  
This natural history provides an opportunity for early detection.  
 
Current Recommendations regarding Screening for IDA or NAID in Primary Care Practice – 
The American Academy of Pediatrics (1998) recommends screening with a hemoglobin or 
hematrocrit at 9-12 months of age and then 6 months later, and, for patients at high risk, once a 
year from age 2-5 years.24  However, both the Canadian Task Force on the Periodic Health 
Examination (1994) and the US Preventive Task Force (2006) have concluded that the evidence 
is insufficient to recommend for or against routine screening for IDA in asymptomatic 
children.25,26  These guidelines have focused on IDA, but have not addressed screening for 
NAID. 
 
Developmental Outcomes of Young Children with Iron Deficiency Anemia – Studies of 
outcomes of IDA have been largely conducted in developing countries due to the high 
prevalence.  Poor developmental outcomes of IDA, which persist long term despite iron therapy, 
have been summarized in two recent reviews of longitudinal observational studies.27,28 In 
addition, case-series and case-control studies suggest an association between IDA and childhood 
stroke (including a publication from our research group).29-34  A Cochrane systematic review 
examined the effectiveness of iron treatment  to improve developmental outcomes.35  Short term 
treatment (5-11 days) examined in five trials (published between 1978 and 1993), including 180 
children with IDA, showed no differences in developmental outcomes.36-40  Two studies 
(published in 1986 and 1993), including 160 children examined longer term treatment (more than 
30 days) and demonstrated improvements in developmental outcomes for the groups receiving 
oral iron treatment versus placebo.41,42  Although the authors of the Cochrane review concluded 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
5 
that there is urgent need for further randomized trials in children with IDA with long term follow 
up, there have been no recent trials; most investigators currently consider the question of the  
association between IDA and development to lack equipoise.   
 
Developmental Outcomes of Young Children with Non-Anemic Iron Deficiency – A graduate 
student and the principal investigator have recently undertaken a systematic review of the 
literature regarding the effectiveness of oral iron treatment to improve the developmental and 
hematologic outcomes of young children with NAID.   From the titles of 743 articles, full text 
review was completed on 46, and two randomized controlled trials were found for preschool 
aged children with NAID treated with oral iron 3-6 mg/elemental iron/kg daily versus no 
treatment.42,43  For both studies, the primary objective was to study children with IDA; however, 
both included children with NAID randomized to oral iron or no treatment, and this data was 
available for the review.  The first study (n=29, conducted in Indonesia, published in 1993) 
showed no statistically significant difference between groups in the post-treatment 
developmental score.42 The second study (n=40, conducted in Turkey, published in 2004) 
showed a statistically significant difference between groups in the post-treatment mental 
developmental score, but not in the psychomotor developmental score.43 Meta-analysis was not 
possible due to significant heterogeneity.  Both studies showed moderate risk of bias due to 
insufficient information regarding allocation concealment and inadequate reporting of 
adjustment for co-variates (notably, socio-demographic variables); furthermore, mothers were 
not blinded in the second trial as placebo was not used.  We have concluded that the 
effectiveness of oral iron treatment in children with NAID to improve developmental outcomes 
remains in question, and with this equipoise it is ethical and urgent to conduct such a trial.  The 
results of a high quality, adequately powered trial, conducted in a developed country will begin 
to establish an evidence base for screening for iron deficiency with an aim to improve 
developmental outcomes. 
 
MEASUREMENT ISSUES  
This section will provide a rationale for our selection of measures for this study.  Our objective 
was to select scientifically sound, parsimonious and pragmatic measures of infant cognition, 
social and emotional behavior, and iron deficiency which may be obtained in the primary care 
practice setting. 
 
Assessment of Infant Cognition – There are several tests of infant cognition from which to 
choose.44  The Mullen Scale of Early Learning (MSEL) 45 has been used extensively in several 
pediatric conditions including autism spectrum disorders, 46 profound hearing loss,47 genetic 
conditions,48-51 biliary atresia,52 language delay,53 and congenital hypothyroidism.54 Although the 
second edition of the Bayley Scales of Infant Development (BSID-II) have been used extensively 
in research and clinical practice for developmental follow up of preterm infants,44 and in several 
studies of IDA,36-40,42,43 there have been concerns regarding limitations of the scale, including 
lack of separate standardized scores for non-verbal performance (for example, low Mental 
Developmental Index scores may reflect a specific delay in communication skills, cognitive 
abilities, or both) and the unconventional structure of the test.44  The third edition of the Bayley 
Scales (BSID-III) attempts to address this limitation; however a recent study demonstrates that 
the BSID-III scale underestimates developmental delay in 2-year-old premature children.55  

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
6 
Furthermore, the MSEL may be used to test children from birth to 5 years 8 months, whereas the 
BSID may be used up to 42 months only.  For all of these reasons, the MSEL has been selected 
as the test of infant cognition to be used in this study. 
 
Assessment of Social and Emotional Behaviour – Although measures of infant cognition have 
been the primary outcomes for studies of IDA and NAID, there is a body of literature supporting 
an association between IDA/NAID and altered infant social-emotional behavior, including 
shyness and frustration, and poor engagement, soothability, and affect.56-58 Several measures of 
social-emotional behavior have been used in these studies; however, there is no clearly 
established measure.  Our research team has recently studied 3-5 year old children using a 
questionnaire called the Child Behaviour Questionnaire (CBQ) and found that children who 
scored highly on the ‘negative affect’ scale of the CBQ were also at high nutrition risk, 
according to a validated questionnaire of nutrition.  The ‘negative affect’ scale includes 
constructs identified as important in studies of children with IDA, including soothability, 
fearfulness, and sadness.  The constructs of regulation captured in the CBQ questionnaires 
appear closely related to social-emotional development in young children. Therefore, we have 
selected the version developed for children aged 18-36 months called the Early Childhood 
Behavior Questionnaire (ECBQ) for inclusion in this proposal.59   
 
Laboratory Assessment of Iron Deficiency Anemia (IDA) and Non-anemic Iron Deficiency 
(NAID) – There appears to be agreement regarding the hemoglobin cut off of >110 g/L to 
distinguish anemia from non-anemia in children 1-3 years of age.  The most significant 
controversy is focused on measures of iron stores.  In a systematic review of 55 studies of adults 
regarding the diagnostic test properties of various measures of iron compared with the gold 
standard of bone marrow aspirate, serum ferritin was identified as the single most powerful test, 
with a likelihood ratio of 51, for a serum ferritin of < 15 µg/L.60 No similar research has been 
done in children.  Population based research from the National Health and Nutrition Examination 
Survey requires 2 of 3 abnormal tests of iron to meet the definition of iron deficiency, which 
avoids the sole use of serum ferritin, as it may be falsely elevated during acute illness. 11,12  In our 
office based research, we exclude children with acute illness, and use serum ferritin as our 
primary measure of iron (mean corpuscular volume is used as a secondary measure).61,62  The 
most commonly used cut-off for  serum ferritin is >12 µg/L for distinguishing iron sufficiency 
and iron deficiency in children 1-3 years.  For the purposes of this proposal, we will use the 
terms iron sufficiency (IS), iron deficiency anemia (IDA) and non-anemic iron deficiency 
(NAID), with laboratory definitions described in methods.  
 
ESTABLISHMENT OF THE TARGet Kids! RESEARCH NETWORK  
The investigators have established a program of research aimed at advancing the scientific basis 
for preventative primary healthcare for young children. The following progress has been made: 
Establishment of a community based primary care research network called TARGet Kids! –
Since September 2008, a conceptual framework of TARGet Kids! has been established (See 
Appendix 1: TARGet Kids! overview), a steering committee formed, practice sites selected, 
equipment purchased, procedures standardized, research staff trained, partnerships established 
with the Applied Health Research Centre (AHRC) at the St. Michael’s Hospital for data 
management and Mount Sinai Services (MSS) for laboratory measurement. Electronic linkages 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
7 
between physician practices, AHRC and MSS have been established to allow secure real time 
transfer of data to our central database.  TARGet Kids! is the only primary care child health 
research network in Canada. 
 
Subject recruitment and data collection through TARGet Kids! – More than 3000 children, 1-5 
years of age have been enrolled in TARGet Kids!, with collection of non-invasive measures 
including questionnaires and physical measures, and more recently laboratory testing has been 
completed in almost 1000 children.  This work provides evidence of feasibility of TARGet Kids! 
as a platform for the current study. (See Appendix 2: Subject recruitment and data collection) 
 
Developing a focus in child development – Since September 2008, TARGet Kids! data collection 
includes the measurement of child temperament through a parent-completed questionnaire (Child 
Behaviour Questionnaire).  We have found that children, 3-5 years, with high ‘negative affect’ 
are at high nutrition risk.  In the current application, we seek to expand our focus in child 
development.  To reach this goal we have established collaborations with researchers in child 
development.  Including a focus in child development in the overall TARGet Kids! initiative is a 
strategic opportunity, given the importance of healthy developmental trajectories as a critical 
outcome measure for children.  
 
RATIONALE FOR A FOCUS OF RESEARCH TO OPTIMIZE EARLY CHILD 
DEVELOPMENT THROUGH SCREENING IN THE PRIMARY CARE PHYSICIAN 
PRACTICE SETTING  
Early detection of non-anemic iron deficiency presents an important opportunity to provide 
effective interventions and improve child developmental outcomes.  Physicians in primary care 
settings are ideally suited to provide this screening.  There are critical gaps in knowledge 
regarding the effectiveness of screening for NAID, which this proposal can address.  This 
proposal brings together a unique collaboration between primary care practitioners and research 
teams with established expertise in preventive child health research, child development, iron 
deficiency, clinical epidemiology and clinical trials methodology, analysis and data management.  
TARGet Kids! is now an established research platform which provides a unique opportunity to 
evaluate screening in primary care physician practice settings.  Integrating the current studies 
into the TARGet Kids! platform is timely and highly efficient.   
 
STUDY OBJECTIVES  
Over-arching objectives –The over-arching aims of this new research collaboration are to 
improve the early childhood developmental outcomes and advance the evidence base for 
screening of children in primary care practice settings.  
 
 
Specific objectives – In young children 18 to 36 months of age, to assess laboratory screening 
for iron deficiency followed by a comparison of the effectiveness of four months of oral iron 
treatment plus dietary counseling with placebo plus dietary counseling, to improve 
developmental and laboratory outcomes in children with non-anemic iron deficiency (NAID). 
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
8 
Research Question (PICOT Format) – In young children 18 to 36 months of age, identified 
with non-anemic iron deficiency (NAID) based on screening at the time of their well-child visit, 
is four months of oral iron treatment plus dietary counseling better than placebo plus dietary 
counseling, to improve developmental and laboratory outcomes? 
 
Hypothesis – We hypothesize that for young children 18 to 36 months of age with non-anemic 
iron deficiency (NAID) four months of oral iron treatment plus dietary counseling is better than 
placebo plus dietary counseling to improve developmental and laboratory outcomes. 
 
TRIAL DESIGN 
 
Design – To assess laboratory screening and the effectiveness of treatment for NAID, a cohort of 
children will be screened and those identified with NAID will be invited to participate in a 
pragmatic, placebo controlled, blind, parallel group, randomized trial. 
   
Pragmatic-Explanatory Continuum – The primary purpose of this trial is to inform clinical 
decision making, and if possible, secondarily to contribute to an explanation of the causal 
association between iron deficiency and child development.  Therefore, according to the 
framework described by Thorpe (co-investigator) and other leading trial methodologists, the trial 
has been designed along the pragmatic end of the pragmatic-explanatory continuum.63 
Specifically, eligibility criteria, participant compliance, follow-up intensity, and primary analysis 
will follow pragmatic approaches (“Does this intervention work under usual conditions?”); 
practitioner expertise and adherence, intervention and outcomes will follow approaches mid-way 
along the pragmatic-explanatory continuum (“Can this intervention work under ideal 
conditions?”) with research assistants undertaking these aspects of the trial.  The investigators 
will report the trial results according to the 2008 CONSORT guidelines for pragmatic trials.64 
 
TRIAL DURATION 
The trial will run for approximately 4 years.  
 
METHODS 
 
Study Setting – The sampling frame will be parents/caregivers of all young children attending 
their well-child visit with their primary care physician.  The study will be set in the offices of 
practices participating in the TARGet Kids! research network (See Appendix 1: TARGet Kids! 
overview) 
 
Eligibility for Participation in the Screening Cohort –  
 
Inclusion criteria: 
1) Age between 18 and 36 months attending any well child visit. 
2) Informed parental consent 
 
Exclusion criteria: 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
9 
1) Previously diagnosed: developmental disorder, genetic, chromosomal or syndromic condition, 
chronic medical condition, (with the exception of asthma and allergies), including chronic 
anemia, iron deficiency or recent oral iron supplementation or treatment 
2) Prematurity with a gestational age less than 35 weeks; low birth weight less than 2500 grams 
3) Attending the office for an acute illness, such as a viral illness, or other health concern other than 
well-child assessment 
4) Any contraindications to receiving elemental iron (i.e. NHP, comparator or placebo) 
5) The use of any NPH containing the same medicinal ingredient(s) as the investigational product 
6) English not spoken to the child in the home or in a child care setting 
 
Eligibility for Randomization – All participants in the screening cohort will undergo laboratory 
testing and children will be assigned to one of three categories based upon the results of their 
hemoglobin and serum ferritin: 
1) NAID (non-anemic iron deficiency) - hemoglobin >110 g/L and serum ferritin <12 µg/L 
2) IDA (Iron deficiency anemia) - hemoglobin <110 g/L and serum ferritin <12 µg/L 
3) IS (Iron sufficiency) - hemoglobin >110 g/L and serum ferritin >12 µg/L 
 
 
Interventions – Children with NAID will be randomized to receive either oral iron treatment 6 
mg elemental iron/kg/day or placebo (equivalent volume) once daily or bid or tid, at the 
discretion of the prescribing study doctor based on the patient's tolerance and preference, for four 
months. Dietary advice will be provided to both the groups.  Dietary advice will include 
recommendations regarding maximum daily cow’s milk intake, varied solid food intake 
including high iron containing foods, and avoidance of foods which reduce iron absorption.  As 
this is a pragmatic trial, no specific strategies will be introduced to improve adherence.  To 
monitor adherence at the end of the trial, parents will be asked to return bottles and the amount 
of iron administered will be calculated based on the volume of solution remaining.  No specific 
criteria will be developed for discontinuation or modification of the interventions, as the dose of 
iron is within the safe and recommended dosages for children.  
 
Investigational Agent 
 
Active Arm: Ferrous Sulfate Oral Solution Drops USP (brand Fer-In=Sol by Mead Johnson); 
Strength: 75mg Ferrous Sulfate/mL = 15mg Fe++/mL; NPN # 00762954; Commercial supply 
donated in kind by Mead Johnson. Blinded over-labeling will be done by the SickKids Research 
Support Pharmacy. 
 
Placebo Arm: The placebo is developed by the Hospital for Sick Children Compounding 
Pharmacy. Contains preserved water (preserved with  sodium benzoate), simple syrup NF, 
denatonium benzoate (for  bitter/medicinal taste) and food colouring (see detailed worksheet); 
similar in colour and taste to active; packaged in 50mL bottles  identical to active Fer-in-Sol 
(empty bottles donated in kind by  Mead Johnson). 
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
10
Both active and placebo arms will be packaged in identical bottles with blinded labels. A 
participant information sheet that contains information regarding the study drug will be provided 
to parents who agree to participate in the trial.  
 
Outcomes – A complete course of iron therapy is 4 months.  Changes in developmental and 
hematologic status may be expected within this time frame.  Outcomes will be measured at two 
time periods: baseline and 4 months after enrollment.  The primary outcome will be the 
developmental score using the Mullen Scales of Early Learning (MSEL).  The secondary 
outcomes will include the behavior measure (Early Childhood Behavior Questionnaire) and two 
laboratory measures (hemoglobin and serum ferritin levels).  The analysis metric will be the 
mean difference in outcome between the treatment and control groups at 4 month follow up, 
adjusting for the baseline measures. 
 
Outcome Measures – 
The following measures will be used in all children enrolled in the screening cohort: 
1) TARGet Kids! child and family characteristics questionnaire – Data on child characteristics 
(including socioeconomic status and ethnicity) as well as family factors (family structure, child 
care and familial illnesses), diet and physical activity, and health will be obtained from a detailed 
60 item questionnaire (adapted from the Canadian Community Health Survey65) which is 
completed by a parent at the time of enrolment.  Questionnaires have been extensively pilot 
tested since September 2008, and numerous modifications have been made to ensure 
understandability and reduce incomplete responses.  
2) The Early Childhood Behavior Questionnaire (ECBQ) – The ECBQ assesses the following 
dimensions in children 18-36 months: Activity level/Energy, Attentional Focusing, Attentional 
Shifting, Cuddliness, Discomfort, Fear, Frustration, High-intensity Pleasure, Impulsivity, 
Inhibitory Control, Low-intensity Pleasure, Motor Activation, Perceptual Sensitivity, Positive 
Anticipation, Sadness, Shyness, Sociability, Soothability.  Parents are asked how often they have 
observed each behavior during the last two weeks, and respond on a 7-point scale (never, very 
rarely, less than half the time, about half the time, more than half the time, almost always, 
always).  The Very Short Form consists of 36 items in 3 broad scales: Negative Affect (12 
items), Surgency (12 items), Effortful Control (12 items).  For each scale, an average is 
calculated, so that the child has a score for each of the 3 scales59. 
3) Laboratory measures – 3 mL of blood is obtained to complete all of the TARGet Kids! laboratory 
measures.  This is well within the acceptable amount for this age group.  The current study 
focuses on laboratory measures of iron status, including hemoglobin, mean corpuscular volume, 
and serum ferritin.  (Separately funded TARGet Kids! studies focus on laboratory measures of 
vitamin D and cardiometabolic status).  Standardized reference ranges will be used to determine 
if the result is normal or abnormal.  
4) Physical measurements – Measurement of height, weight and waist circumference of subjects 
and their accompanying parent, along with child head circumference, is performed using 
standardized anthropometric protocols.66  Weight is measured using a precision digital scale 
(±0.025% SECA, Hamburg Germany) and standing height is measured using a stadiometer 
(SECA, Hamburg Germany). Body Mass Index (BMI) is calculated as weight in kilograms 
divided by height in meters squared and categorized as percentile categories using WHO Child 
Growth curves (which, unlike CDC growth curves, include percentiles for children under 2 years 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
11
of age and are able to monitor the rapid rate of growth in early infancy).67,68  Blood pressure is 
assessed according to the guidelines of the National High Blood Pressure Education Program.69 
 
Additional measures for children enrolled into the OptEC trial 
Mullen Scales of Early Learning (MSEL) – The MSEL assess the cognitive functioning of young 
children from birth to 68 months.  The assessment is based on the child’s responses to activities 
prepared by the trained examiner.  Five skill areas are measured: Gross Motor and four cognitive 
skills (summarized into an Early Learning Composite score) - Fine Motor, Visual Reception, 
Receptive Language, and Expressive Language.  The raw scores for each scale can be converted 
into age-adjusted normalized scores. The four ‘cognitive’ skills score can be converted into a 
normalized ELC score, with a mean of 100 and a standard deviation of 15.45 A participant 
information sheet that contains information regarding developmental testing will be provided to 
parents who agree to participate in the trial.  
 
Pre-study screening and Baseline Measurements 
The baseline data for this trial will be the same data collected during the TARGet Kids! visit of a 
child. In the TARGet Kids! Program parents/caregivers of eligible children are invited to 
participate by letter two weeks before their scheduled well-child visit.  At the time of the 
physician office visit, parents will complete the written consent form, questionnaires (TARGet 
Kids! child and family characteristics questionnaire, ECBQ) and physical and laboratory 
measurements as described above. The overall research plan is shown in a schematic (See  
Appendix 3: Schematic of study plan). A Parent Letter containing a short description of the 
OptEC trial will be given to parents of children enrolled in the TARGet Kids! Initiative and are 
potential candidate for the OPtEC trial. This letter will state that incase found eligible the parents 
will be contacted by phone to invite them to participate in the OptEC trial.  
 
Recruitment Strategy 
TARGet Kids! Network has 6 collaborating primary pediatrician and family medicine practices. 
This trial will be integrated into the current TARGet Kids data collection system and the baseline 
data for this trial will be the same data collected during the TARGet Kids! visit of a child. After 
the physicians receive the lab test results research assistants (RA) will be instructed to contact 
potential participants over the phone. That the RA can contact TARGet Kids participants over 
the phone for participation into future studies have been incorporated into the TARGet Kids 
consent form. When the RA approach the parents over the phone to consider participating in this 
trial the RA will at the same time introduce the OptEC Trial to the parents and request them to 
return to the physician's office if they agree to participate. The RAs will be provided with a 
scripted telephone dialogue in order to standardize the patient recruitment process done over 
telephone. A Screening Form will be used to screen and enroll participants in the trial. At the 
physician's office the RA will review the consent form with the parent. The clinic nurse will 
review the iron status of the child with the parent and obtain informed written consent. The 
family will have the opportunity to ask questions to the RA, the pediatrician and/or office 
nurse/staff at any time. 
 
Participant Timeline 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
12
Participants will be assessed at two time periods: baseline and four months after the baseline 
visit.  The baseline assessment will be carried out in two steps. Step 1: The baseline TARGet 
Kids! Data collection; Step 2: According to the lab test results those who agree to participate in 
the OptEC trial will be asked to come back to the physicians office where the developmental 
testing will be performed. Data (questionnaires, physical measurements, developmental testing 
and laboratory testing) will be collected at both the baseline and follow-up periods.  There is no 
requirement for a run-in period or washout period.   
 
Randomization, Stratification, Blocking and Sequence Generation 
Randomization will be stratified by clinic site.  Block randomization will be generated with 
blocks of variable sizes.  An advantage of block randomization is that group sizes are similar at 
the end of each block enrolled.  The biostatistician will generate the randomization sequence for 
each clinic site using computer-generated random numbers.   
 
Allocation Concealment 
Allocation concealment is the process that prevents any trial participant or investigator from 
knowing in advance the treatment to which subjects will be assigned, and seeks to prevent 
selection bias.  In this study, allocation concealment will be achieved by having the Pharmacy 
Department at the Hospital for Sick Children prepare the treatment and placebo in sealed, 
serially numbered bottles of similar appearance and weight according to the allocation sequence.  
A disadvantage of block randomization is that it may lead to study personnel guessing the 
allocation sequence; to reduce this possibility and to enhance allocation concealment the block 
sizes will be varied. 
 
Blinding  
Parents, attending physicians, laboratory personnel, and study personnel conducting the outcome 
assessments, data analysts and investigators will be blind to the group allocation.  Study 
medication and placebo will be supplied in bottles that look identical, and the appearance, 
consistency and taste of the liquid will be similar.  Group allocation will be concealed until the 
final data analysis is performed. 
 
Non-randomized Children 
Since all children will undergo laboratory screening at baseline, two additional groups of 
children (IDA, IS) will be identified and followed without randomization.  Children with IDA 
will all receive oral iron treatment 6 mg elemental iron/kg/day in 2 divided doses for four months 
plus dietary counseling, which would be considered standard of care.  Children with iron 
sufficiency (IS) will not receive any intervention.  Children with IDA and IS will be included in 
the analysis plan for comparison with the NAID groups. 
 
Data Collection Methods 
Questionnaire data and physical measurements will be collected by the Research Assistants who 
are embedded in the practices.  The Research Assistants have been trained to ensure accuracy of 
data collection and the questionnaires have been extensively pilot tested.  The TARGet Kids! 
Health and Nutrition Questionnaire will be used to collect data only at baseline, a follow-up 
questionnaire will be used at the follow-up visit and the ECBQ will be used both at baseline and 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
13
follow-up visit. Blood work will be obtained by trained personnel according to the arrangements 
established at each of the practice sites; for example at some sites the Research Assistant is also a 
trained Phlebotomist and at some sites the clinic Nurse performs phlebotomy.  Blood testing will 
be performed once during the TARGet Kids! visit and then after four months during the follow-
up visit. The Research Assistant is responsible for ensuring the blood is delivered to Mount Sinai 
Services (MSS) for laboratory testing.  MSS provides customized laboratory and research 
services to pharmaceutical and biotech companies, and researchers 
(http://www.mountsinaiservices.com/pages/Home).  Laboratory results are sent electronically to 
the data management centre (see next section) as well as faxed to the practicing physician who is 
responsible for communicating the results to the participants.  Children eligible for the 
randomized trial will return to the physician’s office where the Mullen Scales of Early Learning 
will be administered by a trained psychometrist under the supervision of one of the co-
investigators who is a developmental psychologist (Dr. Eva Mamak).  This will take 
approximately 30-40 minutes.  At the 4 month follow up visit, the Research Assistant is 
responsible for ensuring that the questionnaires, physical and laboratory measures are completed.  
The psychometrist will complete the MSEL. 
 
Concomitant Medication 
Concomitant interventions permitted include over the counter multivitamins which do not 
contain iron; those prohibited include additional over the counter iron. 
 
Premature Withdrawal Criteria 
1) Participant developing hypersensitivity to the provided syrup 
2) Participant becoming extremely sick 
3) Participant hospitalized for more than a week without signs of improvement 
 
Probable lost to follow-up patients 
Children who fail to  show-up for their 4 month follow-up visit will be contacted initially on 
alternate days up to a period of one month and then on a monthly basis until the end of the 
trial period (4 years) by the RAs over telephone.  
 
 
Unblinding Procedures 
If a subject in the randomized study deteriorates or has persistent, severe bothersome side effects 
then unblinding may be necessary. Emergency unblinding should only be done when the clinical 
treatment of the patient will be different by knowing which arm of the study the patient was on. 
The physician caring for the subject should contact the principal investigator or co-investigator 
first to discuss the unblinding procedure.  The study investigators should remain blinded if 
possible. 
 
Adverse event reporting 
All adverse events will be reported to the Hospital for Sick Children Research Ethics Board 
according to the Hospital for Sick Children’s adverse event reporting requirements. All adverse 
drug reactions to the study medication will be reported to Health Canada within 15 calendar days 
or for death or life-threatening events, within 7 calendar days. In the latter case, a follow-up 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
14
report must be filed within 8 calendar days. Adverse reactions will be managed according to the 
Hospital for Sick Children’s standard clinical management practices. 
 
Sample Size 
From previous research, it is anticipated that the mean MSEL developmental score for children 
with NAID will be 90, and the standard deviation is + 15.41-43 To detect a 6 point difference in 
post-treatment MSEL developmental score between treatment and placebo group, with a power 
of 80% and a significance level of 5% will require a total sample size of 150 (75 per group).  
With an estimated prevalence of NAID of 10%, it is anticipated that screening approximately 
1500 children will identify 150 children with NAID to be randomized over a 4 year period.  
Expecting potential drop-outs and withdrawals to be 0-20% a total of 180 NAID children will be 
randomized. For the non-randomized children (IDA and IS), it is anticipated that the mean 
MSEL developmental score for children with IDA will be 85 and the mean developmental score 
for IS children will be 100 with a standard deviation of + 15.41-43 From the screening cohort of 
1500 it is anticipated that 1-2% will have IDA (n=25) and an equal number of randomly selected 
children with IS (n=25) will be sampled for comparison. To randomly select children with IS,  
once a child with IDA is identified the immediate next child identified with IS and agrees to 
participate will be enrolled in the trial.   
 
Statistical Analysis 
From the screening cohort, the baseline characteristics of the three groups (NAID, IDA, IS) will 
be compared with descriptive statistics and significance testing.  Categorical variables will be 
compared with a chi-square test and that continuous variables will be compared with an ANOVA 
(or non-parametric equivalent).  For the participants with NAID randomized to treatment or 
placebo groups, no significance testing will be performed on the baseline characteristics); 
however, we will note any imbalances that have arisen by chance which may be clinically 
meaningful.  All children with NAID randomized to treatment or placebo will be analyzed in the 
group to which they were randomized following the intention to treat principle.  In the primary 
analysis, the difference in developmental and hematologic measures in children with NAID 
randomized to treatment versus placebo will be assessed using linear regression (ANCOVA 
method) with the initial baseline measures included as the adjusting variable70.  In a secondary 
analysis, additional co-variates of clinical or statistical significance (including, parent education, 
family income) will be included in the model.  The primary analysis will be a fixed effects 
model, ignoring stratification by clinic site.  A secondary analysis will include a confirmatory 
analysis using a mixed effects model with interventions and MSEL scores as the fixed effect and 
clinic site as the random effects.  Although efforts to ensure complete data collection and 
participant follow up will be maximized, analytic strategies to handle missing data will include 
imputation techniques, if appropriate. If >20% of participants are lost to follow-up a per protocol 
analysis will be carried out in addition to the intention to treat analysis. 
 
Data Management 
The Applied Health Research Centre (AHRC) of the Keenan Research Centre, Li Ka Shing 
Knowledge Institute of St. Michael’s Hospital, University of Toronto, will serve as the data 
management centre under the direction of Dr. Mamdani, Director of the AHRC 
(http://www.stmichaelshospital.com/research). AHRC employs state-of-the art web-based data 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
15
management software: Medidata RAVE™ (5.6.3). RAVE™ is a secure encrypted web-based 
clinical trial data management system which is fully configurable and incorporates sophisticated 
data validation rules to ensure high quality data is captured. RAVE™ is a web-based application 
allowing for remote web-based data entry directly from the participating practice sites, and 
facilitates real-time data access. Data from the TARGet Kids! initiative, launched in September 
2008, has been entered into a RAVE™ database and will be leveraged for this study. The 
licensing fee has been paid through previous TARGet Kids! related grants.  
 
Trial Monitoring 
A Data Monitoring Committee is not deemed necessary, as the experimental intervention (oral 
iron treatment 6 mg elemental iron/kg/day given once daily or in 2 or 3 divided doses daily for 
four months plus dietary counseling) is standard of care for children in the same age group with 
IDA and the side effect profile is well known.  In the current study of children with NAID, 
similar side effects are expected and will be collected.  There will be no criteria or plans for early 
trial termination. 
 
SUB-STUDIES OF THE OptEC TRIAL: 
Kawsari Abdullah, MBBS is a Pediatrician trained in Bangladesh and currently a PhD student in 
the Clinical Epidemiology and Health Services Research program in the University of Toronto, 
Department of Health Policy, Management and Evaluation.  Dr. Patricia Parkin is her supervisor. 
In accordance with the Department of Health Policy, Management and Evaluation rules for the 
PhD program she has submitted a proposal for her PhD thesis and the department has accepted 
her proposal. Among the three projects she will carry out for her PhD thesis two of them will be 
undertaken as sub-studies of the OptEC trial. Members of the thesis committee and co-
investigators of the OptEC trial have approved the sub-studies for the PhD student. 
Sub-study #1: Internal pilot study to estimate the sample size for the OptEC trial. 
The estimates we have used for the calculation of sample size for the multi-centre OptEC trial 
are based on literature review It has been shown that sample size estimates based on literature 
review are likely to be considerably less than the true values because the literature tends to report 
more homogenous cases series than will be entered in a large clinical trial, especially an efficient 
one with inclusive entry criteria 71.  Furthermore prior estimates are often obtained from trials 
that may have different study conditions to the trial, for example different patient types, small 
number of centres, different treatment duration 72. Thus the prior estimates obtained from these 
studies may not be representative of the current randomized trial. These potential problems can 
be overcome by the use of an internal pilot study which forms an integral part of the trial itself 
and not a separate study. The methodologic issues associated with internal pilot studies are 
described in the literature of the references. 
 
Objectives of the internal pilot study: 
1. To obtain a reliable estimate of the variance (σ2) of the child development scores 
2. To obtain the baseline to 4 month correlation coefficient of the developmental scores based 
on actual data from patients entered in the trial 
3. To recalculate the sample size of the trial using the estimates of the internal pilot 
4. To determine  pre-randomization feasibility issues 
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
16
Sample size:  
The minimum size for an internal pilot study should be 10 or more patients per intervention 
group. It has been shown that the larger the size of the internal pilot the more the accurate will be 
the estimates and so more appropriate will be the recalculated sample size 71-72. Thus based on 
these facts the sample size may be recalculated after 30 participants have been enrolled in the 
randomized trial.  
 
In order to recalculate the sample size for the OptEC trial using the estimates of the internal pilot 
study, we will not need to break the randomization code. As discussed with the study statistician 
this methodology is in alignment with proper conduct of clinical trials. None of the investigators 
will be unblinded to subjects’ group allocation. 
 
Sub-study #2: The effectiveness of oral iron therapy in improving the growth and 
haematological outcome of pre-school children with non-anemic iron deficiency (NAID): A 
randomized trial.  
 
Research Question in PICOT format: 
P = Pre-school children aged 18-36 months identified as having NAID (defined as serum ferritin 
<12 µg/L and hemoglobin >110 g/L) enrolled in the TARGet Kids! Research Network program  
I = Oral iron (6mg elemental iron/kg/day in two divided doses) plus parental dietary counselling 
C = Placebo plus parental dietary counseling 
O = Hematological indices (serum ferritin and hemoglobin level), Growth parameters (weight 
and height) 
T = Four (4) months 
 
Objective of the study:  
The objective is to evaluate whether oral iron therapy given to pre-school children (18-36 
months) with NAID affects their hematological and growth outcome by comparing those 
receiving either oral iron therapy or placebo for four months (with both groups receiving parental 
dietary counseling). 
 
Sample size:  
The sample for this sub-study will be the first 40 NAID children enrolled in the randomized trial. 
Based on previous literature it has been shown that 1.2 cm improvement in children’s height is a 
clinically significant improvement 73. Thus it has been found that a sample of 40 will have 90% 
power to detect a difference of 1.2 cm improvement in height (with a SD=1), at 0.05% 
significance level. 
 
Analysis:  
An analysis of variance using multiple linear regression procedure to examine the association 
between the post-intervention differences in hematological and growth parameters of the two 
intervention groups will be carried out after adjusting for the baseline growth and serum ferritin 
measurements.  
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
17
Group allocation for the first 40 subjects of the OptEC trial will be identified only for the 
hematological and growth parameters (secondary outcomes) for the analysis of the sub-study. 
This un-blinding will only be made known to co-investigator (KA) who will no longer be 
involved with the ongoing conduct of the trial. Group allocation for the primary outcome of the 
OptEC trial (developmental scores) will remain concealed and will not be analyzed for this sub-
study. This methodology has been verified and accepted by the study statistician and other 
members of the OptEC trial team members.   
 
ETHICAL CONSIDERATIONS  
The TARGet Kids! research platform has been approved by the research ethics board at SickKids, 
as well as the other affiliated sites.  Blood results are provided to the child’s physician within 24 
hours; developmental screening tests will be available immediately and detailed developmental 
assessment reports will be available in 4 weeks. The study will be approved by the Research 
Ethics Board prior to enrolling patients. Many parents and physicians may perceive the 
opportunity for a detailed developmental assessment and detailed laboratory testing to be a direct 
benefit of participation in this study. 
 
Quality Assurance -  
This project will be monitored by the Hospital for Sick Children Clinical Research Continuing 
Review program during the data collection phase of the project. The aim of Continuing Review 
is to ensure that all SickKids researchers are maintaining the highest ethical, scientific and safety 
standards for all study participants, and are in compliance with all relevant SickKids policies, 
provincial and federal legislation, and international guidelines such as ICH- Good Clinical 
Practice. All studies are categorized according to the Continuing Review Matrix based on the 
type of study and the level of risk (I to IV) to research subjects and the Clinical Research 
Monitor will review at minimum 10% of the research subjects’ records for study eligibility, 
informed consent, adherence to study protocol, reporting of adverse drug reactions and adverse 
events, and data quality including computer database security and storage of records. Findings of 
the Continuing Review will be presented to the Research Ethics Board and lead PI in a written 
report, and specific recommendations arising from the report will be implemented in a timely 
manner. 
 
RESEARCH TEAM 
Patricia Parkin, MD is a specialist in Pediatric Medicine at SickKids and Senior Associate 
Scientist in the SickKids Research Institute.  She leads the Pediatric Outcomes Research Team 
and has experience in observational and controlled trials in common problems of childhood in 
diverse clinical settings.  She established the TARGet Kids! initiative along with Catherine 
Birken, MD, MSc and Jonathon Maguire, MD, MSc, who are also specialists in Pediatric 
Medicine, applied health researchers, PhD, C Psych, is a Psychologist at The Hospital for Sick 
Children and Investigator at Sickkids Research Institute with expertise in early child 
development and will supervise all cognitive testing.  Darcy Fehlings, MD, MSc is a 
Developmental Pediatrician and Scientist at the Holland Bloorview Research Institute.  Colin 
Macarthur, MBChB, PhD, is Vice President Research at Holland Bloorview Kids 
Rehabilitation Hospital with expertise in child health epidemiology.  Stanley Zlotkin, MD, PhD 
is a Scientist in the Sickkids Research Institute with expertise in nutrition research, especially 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
18
iron deficiency anemia.  Muhammad Mamdani, PharmD, MPH, is a pharmacist and clinical 
epidemiologist, and the Director of the Applied Health Research Centre and will provide 
oversight of the data management aspects of this study.  Kevin Thorpe, MMath, is a 
Biostatistician at the Applied Health Research Centre, has expertise in clinical trials design, has 
developed the biostatistical plan for this study, and will perform the final analysis for this study.  
Azar Azad, PhD, is the Director of Mount Sinai Services, and will provide oversight of all 
aspects of the laboratory testing and reporting. Parkin, Birken, Maguire, Fehlings, Macarthur 
and Thorpe are all faculty teaching in the Controlled Clinical Trials course at the University of 
Toronto Department of Health Policy, Management and Evaluation.  Collaborators include: 
TARGet Kids! steering committee members: Mark Feldman, MD, Head of Community 
Pediatrics, U of Toronto, and Head of the Section on Community Pediatrics of the Canadian 
Paediatric Society; Moshe Ipp, MD and Brian Chisamore, MD MHSc.  TARGet Kids! 
collaborating practicing physicians: Dr. Sheila Jacobson, Dr. Michael Peer, Dr. Carolyn Taylor; 
Dr. Eddy Lau, Dr. Brian Chisamore, Dr. Sharon Naymark; Dr. Marty Perlmutar, Dr. Joanne 
Vaughn, Dr. Janet Saunderson, Dr. Patricia Neelands, Dr. Anh Do, Dr. Alannah Rosenthal.  
  
TRIAL REGISTRATION 
The trial will be registered with U.S. National Institutes of Health ClinicalTrials.gov, which is a 
registry of federally and privately supported clinical trials conducted in the United States and 
around the world. 
 
KNOWLEDGE TRANSLATION 
This proposal brings together a unique collaboration between primary care practitioners and 
research teams with established expertise in preventive child health research, autism and 
developmental research, child health epidemiology, and clinical trials methodology, analysis and 
data management.  The primary care physician members of TARGet Kids! have participated in 
the early stages of shaping the research process to reach the overarching TARGet Kids! goals.  
Members of the TARGet Kids! network include decision makers and policy makers in primary 
care practice. There is no other current network of primary care practitioners and researchers 
focused on child health in Canada.  Findings from this research will be disseminated directly to 
the physician participants and to their patients.  An annual meeting of all the TARGet Kids! 
practices (physicians, nurses, office staff), research team (investigators, research assistants, 
students), and policy leaders (representatives from Section of Community Paediatrics, Family 
and Community Practice, and parent representatives) will occur.  Parents of participants will 
receive the summary of their child’s developmental assessment, anthropometric measures, and 
laboratory measures, leading to a direct benefit for individual participants. Further downstream 
dissemination to primary care physicians will occur through formal and informal venues at local 
levels, such as educational rounds (for example City Wide Paediatric Rounds, SickKids Annual 
Paediatric Update) and held by local physician groups.   End of grant knowledge will be shared 
with the academic community through publication in relevant journals and presentations at 
national and international conferences Annual Meetings of the Pediatric Academic Societies, and 
the Canadian Paediatric Society), and locally through hospital rounds and presentations.  
Messages will be relevant to professionals working in the fields of pediatrics, family medicine, 
developmental pediatrics, nutrition, nursing, dietetics, and public health.  Information will be 
disseminated to professionals by the research team with colleagues at the Canadian Paediatric 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
19
Society. The principal applicant is a member of the Canadian Task Force for Preventive Health 
Care and will participate in the upcoming guideline development for developmental screening 
and screening for iron deficiency anemia, which are on the priority list of topics for 2011-2012.  
Opportunities for coverage in lay publications and media will be sought using experienced 
knowledge broker at SickKids Department of Public Relations.   
 
SUMMARY AND FUTURE DIRECTIONS 
Early childhood is a critical time of development.  There are large gaps in knowledge regarding 
the effectiveness of strategies for promoting healthy child development in the primary care 
physician practice setting.  This study will focus on evaluating the effectiveness of screening and 
treating children with iron deficiency anemia and non-anemic iron deficiency on child 
developmental outcomes.  Future research includes examining the longer term outcomes of this 
screening strategy, to more fully understand the implications for practice and policy.  For 
example, the TARGet Kids! team has initiated communication with researchers at the Toronto 
District School Board, to explore opportunities to link (via unique identifiers, name and date of 
birth) data from preschool years (from TARGet Kids! data collection) to early school readiness 
(measured by the school board using the Early Development Instrument) and school performance 
(measured by the school board using standardized testing from the Education Quality and 
Accountability Office).  The key strengths of this proposal include an important research 
question, engagement with the primary care health care system, a novel research platform-
TARGet Kids!, and a highly qualified team of experienced and emerging investigators, with 
embedded knowledge translation between practicing physicians, investigators, parents and 
children. 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
20
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Deficiency (OptEC) 
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Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
24
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Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: Pragmatic Randomized Trial of Iron 
Treatment for Young Children with Non-anemic Iron Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
25

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: 
Pragmatic Randomized Trial of Iron Treatment for Young Children with Non-anemic Iron 
Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
26
 

Trial title: Optimizing Early Child Development in the Primary Care Practice Setting: Pragmatic Randomized Trial of Iron 
Treatment for Young Children with Non-anemic Iron Deficiency (OptEC) 
OptEC Trial Protocol: February 11, 2012 
27
Appendix 3: Schematic of study plan