Population Health, Biological

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Population Health, Biological Embedding the
Early Years
Clyde Hertzman
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Gradient in all Cause Mortality UK Whitehall
Study
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CHD Mortality - UK Whitehall Study
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The Challenge of the Gradient

• ubiquitous in wealthy and majority world
  countries by income, education, or occupation
• cuts across a wide range of disease processes
• not explained by traditional risk factors
• replicates itself on new conditions as they
  emerge
• occurs among males and females
• flattens up
• begins life as gradient in developmental health

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• Equity from the start

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Sensitive Periods in Early Brain Development
Pre-school years
School years
High
Numbers
Peer social skills
Symbol
Sensitivity
Language
Habitual ways of responding
Emotional control
Vision
Hearing
Low
1
2
3
7
6
5
4
0
Years
Graph developed by Council for Early Child
Development (ref Nash, 1997 Early Years Study,
1999 Shonkoff, 2000.)
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Disparities in Early Vocabulary Growth
College Educated Parents
1200
Working Class Parents
600
Cumulative Vocabulary (Words)
Welfare Parents
200
16 mos.
24 mos.
36 mos.
Childs Age (Months)
Source Hart Risley (1995) Slide by The
National Scientific Council on the Developing
Child
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Estimated Cumulative Difference in Language
Exposure by 3 Years of Age
Million
50
40
High SES
30
Words
Medium SES
20
10
Low SES
0
0
12
24
36
Age of child in months
Source Hart Risley (1995)
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Canada Vulnerable by SES
Percentage
Source NLSCY/UEY 1999-2000 EDI 1999-2000
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Numeracy Scores for Youth 16-25 (IALS 1994)
Source OECD, 1995
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Contributions to Self-rated Health at Age 33 1958
Birth Cohort
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Contributions to Self-rated Health at Age 33 1958
Birth Cohort
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Contributions to Self-rated Health at Age 33 1958
Birth Cohort
pathway/cumulative OR6.15
latent OR5.03
ORn.s.
Birth
Death
OR2.05
intersecting OR3.83
OR1.87
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Problems Related to Early Life

• School Failure, Teen pregnancy,
• Criminality
• Obesity, Elevated Blood Pressure, Depression
• Coronary Heart Disease, Diabetes
• Premature Aging and Memory Loss

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Two approaches

• understanding ECD at the level of the
  population
• understanding the developmental biology of
  the gradient

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The Early Development Instrument A McMaster
Invention!
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A Population Based Measure
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What Does the EDI Measure?
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All BC Kindergarten Children Included
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Introduced in 2000
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500 Initiatives
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EDI Completion in Canada, 2000-2008
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J. Lloyd (December 1, 2008)
Where are we?
Not yet available
We already have
Were applying for
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Kindergarten to Grade 4 EDI to FSA (like the
EQAOs)
of EDI Vulnerabilities
Not passing (kindergarten)
(Grade 4 FSA) Numeracy 0 12.
3 1 22.2 2-3 4 years go by.
33.8 4-5 55.6 Reading 0 17.8 1
33.9 2-3 43.1 4-5 68.3
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Kindergarten to Grade 4 Trajectories by
Neighbourhoods
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• Strategic Goal 1 To realize a comprehensive,
  national system of monitoring and reporting on
  childrens well-being development.

No data, no problem no problem, no action!
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Two approaches

• understanding ECD at the level of the
  population
• understanding the developmental biology of
  the gradient

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Hypothesis Biological embedding

• Biological embedding occurs when
• experience gets under the skin and alters human
  biodevelopment
• systematic differences in experience in different
  social environments lead to different
  biodevelopmental states
• the differences are stable and long-termthey
  influence health, well-being, learning, and/or
  behaviour over the life course.

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SES Differences in Prefrontal Cortex Activity by
School Age
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-002
Emotional Stimulus
HPA Pathway Control
Amygdala
Hippocampus


-
-
Hypothalamus PVN
Cortisol
Cortisol
CRF
PIT
ACTH
Adrenal Cortex
LeDoux, Synaptic Self
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1958 British Birth Cohort Cortisol patterns at
age 45 and math scores at age 7-16 Men
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03-089
Serotonin Transporter Gene Experience in Early
Life - Depression Age 26
Depression Risk
.70
SS
S Short Allele L Long Allele
.50
SL
LL
.30
No Abuse
Moderate Abuse
Severe Abuse
Early Childhood
A. Caspi, Science, 18 July 2003, Vol 301.
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Psychobiological Reactivity and Health among
Children and Macaques(Boyce WT, et al.,
1994-2004)

• Multiple samples of 3-8 year old children
• Troop of rhesus macaques
• Naturally occurring stressors and supports within
  epidemiologic study designs

• Internalizing Behavior Problems
• Respiratory Illnesses
• Injuries in Children
• Violent Injuries in Rhesus Macaques
• Memory for Stressful Events

Supportive
Stressful
Social Context
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Biological Sensitivity to Social Context
Social Stratification, Health and Development
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Epigenetics

• Alterations to the DNA, other than changes to the
  genes themselves, that
• are passed on with cell division
• can change normal gene expression
• can be caused by (early) experience

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• Most well-studied epigenetic mechanism
  methylation of cytosine on the DNA
• If methylation occurs in an active stretch of
  DNA, especially a promoter region, gene
  expression will likely change

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• Whats new about this?
• It does not only occur during basic fetal
  development, when cells are specializingit can
  continue after birth and be influenced by the
  broader environment!

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Epigenesis at Work?
Rats Mothers licking pups Monkeys
Humans
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Gene Transcription Maternal Behavior in the
Rat(Meaney M, Szyf M et al, 2004-08)
Low parental licking and grooming
DNA methylation at GR promoter
?Epigenetic expression of GR
Pregnancy
Upregulation of HPA axis reactivity
Relegation to subordinate roles
Behavioral inhibition
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The Meaney-Szyf Paradigm I

• rat pups from high and low licking/suckling
  mothers cross-fostered to remove genetic effect
• differential qualities of nurturance occurs
  during sensitive period of brain development
• differential nurturance leads to epigenetic
  modification of key DNA regulatory loci through
  methylation

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The Meaney-Szyf Paradigm II

• epigenetic modification leads to lifelong change
  in HPA axis response to stress
• this change affects learning and behaviour across
  the rat life course
• inter-generational transmission (high licked
  female pups become high licking mothers, and vice
  versa)

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Epigenesis at Work?
Rats Mothers licking pups Monkeys Peer
vs mother rearing Humans
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Epigenesis at Work?
Rats Mothers licking pups Monkeys Peer
vs mother rearing Humans - Suicide brains,
1958 British Birth Cohort
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Differences in methylation of the promoter of the
rRNA genes in hippocampus suicide and control
subjects
Szyf, unpublished
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1958 Cohort -- Hypothesis Generating Expedition

• Plan
• examine gt20,000 regulatory regions of 40
  members of the 1958 British Birth Cohort using
  blood collected at 45y.
• Outcome
• approximately 1500 loci are differentially
  methylated according to extremes of childhood,
  but not adulthood, SES

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