A presentation by Shane Norris as part of the Innovations in Design and Measurement panel discussion at the International Symposium on Cohort and Longitudinal Studies in Developing Contexts, UNICEF Office of Research - Innocenti, Florence, Italy 13-15 October 2014

1. Biomarkers, genetics, epigenetics &
metabolomics: Experience from the
Birth to Twenty Plus cohort
Shane Norris
MRC/Wits Developmental Pathways for Health Research
Unit

2. Biomarker
The term “biomarker” was introduced in 1989 as a Medical
Subject Heading term (MeSH) – measurable and quantifiable
biological parameter
In 2001, an NIH working group standardized the definition of a
biomarker as “a characteristic that is objectively measured and
evaluated as an indicator of normal biological processes,
pathogenic processes, or pharmacologic responses to a
therapeutic intervention” - biosample (as a blood, urine, or tissue
test), or recording obtained from a person (blood pressure,
ECG), or it may be an imaging test (echocardiogram or CT scan)

3. Birth to Twenty PLUS
Prospective birth cohort (Johannesburg-Soweto; South Africa)
Recruited 3273 mothers and babies (households) in 1990 to
understand growth and development in a transitioning urban
setting
70% (67%) still in contact with the study
21 data collection waves completed
recently completed the age 22-24 year survey
3 generations
approx 720+ 3G babies

4. Birth to Ten
Biomarkers
1990: Cord blood
1995: Fasting blood sample
(insulin, glucose, lipids)
Blood pressure
1997: Blood pressure
2000: Blood pressure

5. Birth to Ten
Biomarkers
1990: Cord blood
1995: Fasting blood sample
(insulin, glucose, lipids)
Blood pressure
1997: Blood pressure
2000: Blood pressure
Samples
thrown away

6. Birth to Twenty
Biomarkers
2011 onwards Wellcome Trust Funding
Generation 1 (mothers) & 2 (index participant) multiple waves:
• DXA body composition and hip & spine bone mass/density
• Ultrasound abdominal adiposity assessment
• Skeletal maturity (bone age hand x-ray)
• Blood pressure (central blood pressure; 24hr monitoring)
• Respiratory function
• Biobank
• Fasting blood samples
• Urine samples
• DNA

7. Birth to Twenty
Benefits
• Detailed phenotype & biobank - unique
• Developed capacity to implement such measures
(infrastructure, standard operating procedures )
• Ethics – participant understanding, consent, delegation to
ethics committee
• Respond to the emergence of new biomarkers (In adults,
homocysteine more predictive power than the Framingham risk
score – cardiovascular mortality)
• Replace/supplement questionnaires
• Cotinine (smoking)
• Objective measures of physical activity (Actigraph)
• Objective measures on nutrition (vit D; Na/Cr; K/Cr)

8. Birth to Twenty
Opportunities
• Collaboration with geneticists – studies on African population
genetics; obesity, body composition, bone health,
pharmocogenetics (GWAS, metabochip, metabolomics)
• Multi-site study collaborations – NIH/Wellcome Trust H3A
(Human Heredity and Health in Africa)
• 6 African Site study on the genetics of obesity (n=12000)
• Birth to Twenty mothers
• H3A broader network – all studies involved (harmonisation;
maximal benefit, governance, open access to data, central
biobanks, bioinformatics, capacity development, etc)
• Consortia – contribute samples (need for large numbers);
African Genome Variation Project

9. Birth to Twenty
Opportunities
• Epigenetics = mechanism by which environmental factors can
affect physiological function and disease risk
• Study designs that make use of multiple time points are being
increasingly recognized as the most suitable to analyze the
epigenetics of common complex diseases
• Birth cohorts - intergenerational epigenetic studies (pregnant
women & offspring)

10. Birth to Twenty
Opportunities
• Early life biomarkers that are good surrogates for later life
outcomes
• HAPO study of Gestational Diabetes (C-peptide, neonatal
anthropometry & body composition) – adolescent follow-up
• Critical for early life interventions that cannot wait 20+ years to
confirm impact on outcome
• Technology rapidly developing – more objective measures,
easier repeat measures (mobile phones; personal devices, etc)
• New standards – ultrasound foetal growth curves

11. Birth to Twenty
Challenges
• Ethical, legal and social issues
• Community engagement
• Provision of clinical care
• “Blanket” consent & ethics committees
• Country specific regulations of receiving or sending
biological samples
• Multi-site pooled analyses – harmonisation (COHORTS)
• Capacity (INDEPTH sites)
• Costs – once off, maintenance, test costs (but get quicker, less
sample volume and less expensive0

12. Conclusion
• We have used the Bt20 cohort experience to inform current and
future studies – The Soweto First 1000 Days Cohort inclusion
of much more detailed biomarkers to understand how maternal
factors and morbidities (HIV, GDM, obesity, etc) impact foetal
growth, delivery outcomes, neontal and infant growth, body
composition and development.
• Longitudinal cohorts can offer a great deal in the context of
epigenetic epidemiology - better understanding of the
epigenetic patterns and how changes occur in response to a
wide range of environmental, lifestyle, and behavioral factors