Aligning Studies for a Common Goal
DEVOTION Network members are part of 3 unique clinical cohorts. The iCARE cohort consists of youth with type 2 diabetes (T2D) that have been extensively phenotyped to identify early risk factors and biomarkers of kidney complications. The cohort is currently expanding to include children with T2D from 8 sites across Canada, increasing the number of participants enrolled to >400 by the end of the funding period (2020). The Next Generation cohort is a prospective birth cohort which aims to determine the effect of in utero exposure to maternal type 2 diabetes on health consequences of offspring including; obesity, diabetes and cardiometabolic disease. The cohort currently consists of First Nations women with T2D and their offspring and has recently expanded to include First Nations women with gestational diabetes and normoglycemic pregnancies and their offspring for comparison. The overarching goal is to identify the unique modifiable risk factors impacting infants exposed to type 2 diabetes in pregnancy to inform long term screening and prevention strategies. The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study is Canada’s largest general population pregnancy cohort. The CHILD Study was designed to examine the influences of genetic predisposition and environmental factors on children's development. Participants have been followed and extensively phenotyped since before birth to characterize maternal and infant health, nutrition, medication use, stress and the home environment. Clinical assessments were performed at 1, 3 and 5 years of age. An extensive collection of biological samples are available for analysis, including: maternal blood during and after pregnancy, cord blood, breast milk, and child blood, urine, stool and nasal swabs at multiple time points from birth to 5 years.
DEVOTION members are harmonizing data collection within these cohort studies and animal models of chronic disease outlined in the Basic Science Pillar to maximize the capacity for translation of findings between pre-clinical models and clinical cohorts. Using Next Generation Sequencing, large scale epigenetic and microbiota analyses of samples will be conducted to discover biomarkers and mechanisms for the programming of risk for chronic disease early in life.
Improving Renal Complications in Adolescents with Type 2 Diabetes Through Research
The iCARE study was designed to address the extremely high rates of early kidney damage in youth with type 2 diabetes.
This study has recently expanded to include national cohorts, and the revised objects are;
1) Characterize the primary bio-psycho-social (BPS) risk factors associated with prevalent and progressive albuminuria,
2) Determine individual, family and community level factors that influence biological and psychological risk factors and behaviours (adherence) that could be modified to protect against prevalent and progressive albuminuria,
3) Determine if systemic renal inflammation is the common pathway through which BPS risk factors lead to albuminuria in youth with type 2 diabetes.
Next Generation Study
The Next Generation Study started in 2003 when the doctor’s at the children’s diabetes clinic noticed that the children born to parents with childhood-onset type 2 diabetes were also developing type 2 diabetes but at a younger age than their parents. The average age of diagnosis in this study is 12 years, with the youngest child diagnosed at the age of 6.
The Next Generation Study’s goal is to figure out why children are developing type 2 diabetes and to stop this from happening in the future. We want to follow all pregnant women from Indigenous backgrounds throughout their pregnancy and follow their children annually to screen them early for type 2 diabetes. This screening is not usually done during a regular nurse or doctor visit. All the results we receive for each child are explained to the parent/guardian and sent to them for their records.
Canadian Healthy Infant Longitudinal Development Study CHILD
CHILD will provide a greater understanding of the root causes of allergy, asthma, obesity and other chronic conditions by examining gene-environment interactions in the developmental origins of health and disease. This longitudinal birth cohort study involves 3500 families with children born from 2009-12, recruited during pregnancy. The CHILD Study is multi-centre, multi-institutional and multi-disciplinary.
The study involves 44 researchers at 7 universities and 11 hospitals in 4 provinces in Canada. The Manitoba CHILD site, involving 1000 families, is led by members of the Biology of Breathing research team (Drs. Becker and Azad). Participants have been extensively phenotyped to characterize maternal and infant health, nutrition, medication use, stress and the home environment. Clinical assessments are performed at 1, 3 and 5 years of age. An extensive collection of biological samples are available for analysis, including: maternal blood during and after pregnancy, cord blood, breast milk, and child blood, urine, stool and nasal swabs at multiple time points from birth to 5 years.
More information is available at: www.canadianchildstudy.ca
Non-alcoholic fatty liver disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes. The current project is designed as a 30-day pilot trial to demonstrate proof of principle of resveratrol in the population to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity, and to determine the effectiveness, safety, tolerability and feasibility for a larger trial.
The primary objective is to evaluate a twice daily supplementation of resveratrol for safety and tolerability in an overweight and obese adolescent population with NAFLD. Secondary objectives are to evaluate efficacy of resveratrol for reduction of fatty liver and cardiac triglyceride content, as well as whole body insulin resistance and lipid metabolism in overweight and obese adolescents with NAFLD. We also want to evaluate the effects of resveratrol on cardiac function and morphology, serum markers of inflammation, and anthropometric measures in this population.
Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Network
Can-SOLVE CKD is one of five successful recipients of funding through the Canadian Institutes of Health Research’s Strategy for Patient-Oriented Research (SPOR). The Can-SOLVE CKD initiative, which is a unique and innovative partnership of patients, researchers, heath care providers, policy makers, industry and renal agencies that will create a powerful patient-oriented research network to transform the care of people affected by kidney disease.
The Can-SOLVE initiative will ensure that by 2020, every Canadian with, or at high risk for, chronic kidney disease will:
receive the best recommended care,
experience optimal outcomes, and
have the opportunity to participate in studies with novel therapies, regardless of age, sex/gender, location or ethnicity.
The work that will be undertaken over the next five years will fall into three thematic areas:
Identify and support people living with kidney disease who are at highest risk for poor outcomes;
Test and define the best treatments to improve outcomes and quality of life;
Define the best ways to deliver patient-centered care in the 21st century.
Understanding the Origins and Development
The Basic Science Pillar utilizes cell-based and rodent models to identify novel biomarkers and pathways of chronic disease development. We also integrate information from clinical and population health pillars to evaluate causation and validate markers of clinically relevant markers of chronic disease risk. We use state of the art imaging, physiological testing, molecular biology and metabolic core facilities in the Children’s Hospital Research Institute of Manitoba to dissect the mechanisms through which early life exposures affect a child’s risk for chronic disease.
How can microRNAs - small pieces of genetic code that function as gene regulators - disrupt abnormal lung development in babies born with a hole in the diaphragm?
Every day, 150 babies are born with a hole in the diaphragm and abnormal lung development, a disease known as congenital diaphragmatic hernia (CDH). We currently do not know why their lungs develop abnormally. It is important to investigate this, since 1/3 of these babies die from respiratory problems after birth. In our laboratory, we have identified a small piece of genetic code - a microRNA called miR-200b - that might play a very important role during the abnormal lung development in CDH babies.
We will investigate how miR-200b regulates lung development and how disrupted miR-200b abundance leads to abnormal lung development in CDH. Our studies will help to better understand lung development in CDH and we will use this information to plan future therapies aimed at improving lung development in these babies before they are even born.
The Impact of Human-derived Human Milk Fortifiers (H2MF) on Gut Microbiota Development and Oxidative Stress in Premature Infants:
Breastmilk provides the best nutrition for healthy infants, but breastmilk alone cannot meet the unique nutritional needs of very small premature newborns. These infants require milk supplemented with fortifiers (HMF), which have traditionally been made from cow milk. However, cow milk alters the gut microbiota and causes oxidative stress in young infants. New fortifiers made from human milk (H2MF) have recently become available, but are not widely used in Canada. Ours will be the first study to study the effect of new H2MF on gut microbiota and oxidative stress in premature infants.
This research will help inform feeding recommendations for premature infants and guide the development of improved milk fortifiers in the future.
Investigating the developmental origins of childhood obesity - Environment, Genes & Chronic Disease (EGCD):
Obesity is the fastest growing chronic illness in Canada, not only among adult men and women, but also in pregnant women and children. Pre-pregnancy obesity is a factor that increases the likelihood that a woman will develop diabetes during pregnancy. In turn, exposure to diabetes during pregnancy influences the risk for obesity development in children, according to recent findings.
Our understanding of how a mother’s diabetes during pregnancy influences the development of obesity in children is incomplete. We plan to study populations of children and their mothers in combination with rodent models of diabetes during pregnancy, to determine how the maternal environment influences the development of obesity in their children. Our research aims to identify new biomarkers of obesity risk that could be used to prevent the extensive health and financial burden of obesity in children and future generations.
June 2016 Catalyst Grants
1) Natural health product intervention during diabetes in pregnancy – Grant Hatch, Vern Dolinsky, Christine Doucette
This study will test the hypothesis that supplementation of gestational diabetes-inducing high fat and sucrose diets with resveratrol or berberine during pregnancy prevent adverse health outcomes in the offspring (e.g. neurocognitive deficits, cardiovascular, chronic lung and metabolic diseases) via improved mitochondrial function and reduced oxidative stress/inflammation.
2) 5 hydroxymethylcytosine in nuclear and mitochondrial DNA – Jim Davie, Vern Dolinsky, Joe Gordon, Brandy Wicklow
This study will test the hypothesis that incorporating the epigenetic signature of 5 hydroxymethylcytosine of nuclear and mitochondrial DNA from white blood cells with that of nuclear 5 methylcytosine will produce a superior biomarker. The aim is to determine which of the multitude of methods to determine the nuclear and mitochondrial genomic 5 hydroxymethylcytosine is most efficient, reliable and cost effective.
3) Assessing asthma risk with gestational diabetes in murine models – Andrew Halayko, Vern Dolinsky, Christopher Pascoe
The first aim of this study is to develop the first mouse model of house dust mite sensitivity for use in determining asthma risk following environmental exposures. The second aim is to determine whether maternal diabetes during pregnancy affects the risk for house dust mite -challenged induced airway hyper-responsiveness and inflammation in offspring.
4) To evaluate the effects of antenatal and post-natal statin therapy in an animal model for abnormal lung development and congenital diaphragmatic hernia – Richard Keijzer, Aruni Jha, Nagmeh Khoshgoo
The objective of this study is to evaluate the effects of antenatal and postnatal statin therapy in an animal model for abnormal lung developmental and congenital diaphragmatic hernia.
5) Epigenetic mechanisms and associations with septo-optic dysplasia: a pilot project – Celia Rodd, Brandy Wicklow, Asis Mhonni, Pinzhoo Hu
This study is a pilot project to assess methylation of cytosine in CpG dinucleotide patterns in genome-wide methylation analysis in children with septo-optic dysplasia. It tests the hypothesis that children with optic nerve hypoplasia/septo-optic dysplasia spectrum will have differentially methylated CpGs and differentially methylated regions between this disease and controls.
Mentorship and Education for Youth and Generations
Working closely with communities, stakeholders, experienced early child education programs and policy makers, our formative work supports the design of interventions that will improve early childhood health. Working closely with Rob Santos from Healthy Child Manitoba, our team will help to move discoveries into evidence based decision making and rapidly develop policies or programs for improving child health. Our current projects include:
PAX Good Behavioural Game
North End Wellness and the Winnipeg Boldness Project
Aboriginal Youth Mentorship Program (an affliated project)
Aboriginal Youth Mentorship Program:
AYMP was developed as a school-based program designed to reduce the risk of type 2 diabetes in Indigenous youth. The program is designed to create mentorship relationships between elementary and high school students by using the principles of the Circle of Courage to share knowledge of healthy food and activities.
This program relies on high school students as mentors to run all of the activities, with the supervision of and adult mentor. The youth mentors meet before the program in order to plan activities, and on the program day mentors prepare the snack, set up the gym for the activities, run the program, and do all of the clean-up. AYMP started as a one site study but has evolved into a program that can be found in 5 locations within Manitoba, and more recently has been approved to expand nationally to 7 more sites.
Factors Affecting the Inadequate Prenatal Care Among Women in Northern Manitoba:
Despite Canada’s universally funded health care system, prenatal care utilization varies widely across the province with the highest rates of inadequate prenatal care found in northern Manitoba. Prenatal care (PNC) has the potential to reduce perinatal morbidity and mortality by treating medical conditions, identifying and mitigating risks, and helping women to address behavioral factors that contribute to poor outcomes. Although research has been conducted in inner-city Winnipeg on the determinants of inadequate PNC, little is known about the determinants of inadequate PNC in Northern Manitoba. The purpose of this study is to identify barriers, motivators, and facilitators related to the use of prenatal care among women living in Northern Manitoba. This study is using a mixed-methods design, consisting of both a quantitative (case-control study) and a qualitative component (descriptive exploratory study).
The case-control study will identify factors related to inadequate PNC among women delivering in Thompson, The Pas and Flin Flon by comparing demographic characteristics and barriers and motivators associated with PNC use among women who received inadequate PNC (cases) and those who received adequate PNC (controls). The descriptive exploratory component will use in-depth interviews to explore women’s perceptions of barriers and motivators to obtaining PNC and service providers’ perceptions of barriers and facilitators to obtaining PNC and suggestions for improving use of PNC. Data collection for the case-control component is in progress, and interviews for the qualitative component will begin in October. Knowledge gained from this study will be used to design interventions to improve use of PNC by women in the North. The study is being guided by a team of investigators, decision makers/knowledge users, and stakeholders.
PAX – Good Behavior Game:
The PAX Good Behavior Game (PAX GBG) is a classroom-based intervention to create an environment that is conducive to learning and improves self-regulation, which is a behavior highly associated with positive social outcomes in life. More recently, leading scientific experts in the area of self-regulation suggest that these behaviours may also be protective against obesity and obesity-related diseases. In the 2011/2012 school year, the Manitoba Government launched PAX, a first-of-its-kind, province wide pilot project offering Grade 1 teachers the training and tools to help thousands of children develop social, emotional and self-discipline skills.
The 2-year randomized trial of 5000 grade 1 students within 200 schools in province of Manitoba was conducted thanks to a $1.3 million investment form the Province of Manitoba. Schools from across Manitoba, including First Nation and independent schools, participated in the trial. Pilot data suggest that this curriculum that promotes self-regulation, significantly improves academic outcomes while reducing poor conduct, behavioral problems and bullying. Students involved in the trial were ~ 6 years of age during the intervention (2012) and will be 10-11 yrs old in 2015/16.
We will recruit 400 children (200 controls and 200 intervention) from the original PAX GBG trial living within 500km of Winnipeg to CHRIM for measures of chronic disease risk. We will oversample Aboriginal youth to ensure adequate power for sub-group analyses. We will assess obesity status, adiposity, fasting glucose, insulin, lipoprotein profiles, blood pressure, physical activity levels, diet and sleep patterns using standard techniques. We will also be able to assess methylation patterns of genes associated with chronic disease.
Data Collections and Strategies for Success
Observational studies are essential to human developmental origins of health and disease (DOHaD) research, requiring detailed and longitudinal health data throughout the life course, from conception to adulthood. Our cluster will build on existing infrastructure to enhance capacity for observational DOHAD research by leveraging and expanding population health databases held in the Manitoba Population Research Data Repository at the Manitoba Centre for Health Policy. New datasets required for DOHaD research will be incorporated into the Repository, including clinical data from neonatal intensive care units and pediatric primary care providers, routinely collected infant feeding data, and child health survey data from First Nations communities. In addition, clinical cohorts (e.g. the Manitoba CHILD and NextGen pregnancy cohorts) will be linked into the Repository, facilitating: a) measurement of key DOHaD exposures and clinical outcomes that are not captured in cohort data; b) extended follow-up of cohort participants through administrative data; and c) validation of case definitions using administrative data. Finally, our pillar will advocate for the abstraction of key DOHaD variables that are not currently captured in the Repository (e.g. maternal pre-pregnancy BMI and gestational weight gain).
Manitoba Infant Feeding Database:
This is a population-based data file capturing infant feeding information collected at routine vaccination visits. A pilot test of the data collection strategy following infants from birth until six months of age has been conducted.
The data collection will now continue until the infants’ first birthday. Having longitudinal infant feeding data routinely collected and housed at the Manitoba Centre for Health Policy will facilitate important research on the relationships between infant feeding, maternal/child health outcomes, and the social determinants of health. This type of infant feeding database is the first of its kind in Canada.
The Biology of Breathing Theme began in March 2003 and was the first theme-based research group at the Children’s Hospital Research Institute of Manitoba.
The formation of this theme consolidated a broad spectrum of local research strength in pediatric lung health and disease and includes: more than 15 principal investigators and collaborating investigators working in concert to carry out world-class research in pediatric pulmonary disorders.
This includes five core research facilities that provide capacity spanning molecular biology and lung physiology assessment; and offers an interactive, multi-disciplinary training program for basic and clinical trainees that is linked to nationally supported research training networks.
Biology of Breathing includes four research areas of broad and complementary scope:
Asthma Prevention, Diagnosis, and Treatment
Smooth Muscle Biology in Lung Health and Disease
Novel Animal Models of Human Lung Disease
Biology and Disease in the Developing Lung
For additional information about the Biology of Breathing Research Theme, visit their website: http://chrim.ca/research/biology-of-breathing/overview/
Dr. Andrew J. Halayko, Theme Leader
Gestational and Pregestational Diabetes Exposure in Utero: Validation if a Definition for use in Administrative Data:
Given the potential differences in effects of gestational and pregestational diabetes on fetal development and long term metabolic health, it is imperative to have a validated definition that differentiates gestational and pregestational diabetes in large administrative databases. Using administrative data in the Population Health Research Data Repository at the Manitoba Centre for Health Policy linked with the Diabetes Education Resource for Children and Adolescents Database, we will determine the best administrative definition for gestational and pregestational diabetes.
Research using these definitions will help advance our understanding of both the short and long term effects of exposure to diabetes in pregnancy (both gestational and pregestational exposure).
Type 2 diabetes is the fastest growing chronic illness in Canada. In 1985, a girl from northern Manitoba came to our hospital in Winnipeg with diabetes that was very different from the typical type of diabetes seen in children. This may have been the first case of Type 2 diabetes in a child in Canada.
Manitoba currently has one of the highest rates of Type 2 diabetes in children in the world and the number of children in Manitoba with Type 2 diabetes, is 12 times higher than any other province in Canada.
Our mission is to create an environment and provide the infrastructure to support state-of-the-art epidemiological and basic science research in the area of obesity and T2D complications in youth.
Dr. Jon McGavock, Theme Leader