AEPI55D

1. Chronic Disease : What
comes after risk factor
epidemiology?
William McClellan, MD, MPH
Professor of Medicine and Epidemiology
Emory University

2. www.smj.org.uk/0803/CHD%20figure_1.htm .
Trends in coronary heart disease mortality
among men aged 35-64 in selected
countries/areas

4. Remaining lifetime risks for atherosclerotic CVD in
men and women at 50 years of age.
Optimal risk factors (RFs) are defined as untreated total cholesterol <4.65
mmol/L (<180 mg/dL), untreated blood pressure <120/<80 mm Hg,
nonsmoker, and nondiabetic.
Circulation. 2010; 121: 1768-1777

5. Lipoprotein-associated
Apolipoprotein B
Lipoprotein (a)
LDL particle size
LDL particle number
Triglycerides
Cholesterol ester transfer protein level
Lipoprotein-associated phospholipase A2
Small-dense LDL
Oxidized LDL
Apolipoprotein A1
Paraxonase-1
Inflammatory
C-reactive protein
Interleukin-18
Interleukin-6
Interleukin-10
Tumour necrosis factor-a
Serum amyloid A
Serum inter-cellular adhesion molecule-1
Myeloperoxidase
sCD40
Vascular cell adhesion molecule
Interleukin-1 receptor antagonist
Thrombosis-related
Fibrinogen
Fibrin D-dimer
Plasminogen activator inhibitor-1
von Willebrand factor
Soluble CD40 ligand
Homocysteine
Factor VIII
Others
Matrix metalloproteases-9
Tissue inhibitor of metalloproteinases-1
Natriuretic peptides
Insulin
E-selectin
Adiponectin
Leptin
Ferritin
Fasting glucose
Hemoglobin A1c
Urinary albumin
Non-Framingham Risk Factors

6. Nature. 2011 Apr 7;472(7341):57-63. doi:
[PubMed - in
S
Intestinal microbial metabolism of phosphatidylcholine an
Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, F
N Engl J Med. 2013 Apr 25;368(17):1575-84. doi: 10.10
Systems biology: Detailed, integrated, orthogonally
linked networks at each level of biological organization
Biological organization
• Genes
• Transcript
• Protein
• Metabolite
• Organelle
• Cell
• Organ
• Organism
• Social System
• Ecological systems
Recent applications
•Geospatial variations and
hierarchical models
• Complex biomarkers
– Genome
– Proteome
– Metabolome
– Microbiome
• Non-linear causal networks
•Chronic disease surveillance and T2
translation
•Evidence-based public health
practice

7. Integrated biological systems

8. Heart disease death rates are spatially smoothed to enhance the stability of rates
in counties with small populations. Deaths are defined according to the following
International Classification of Diseases (ICD) codes:
ICD-9: 390–398, 402, 404–429; ICD-10: 100–109, I11, I13, 120–151.
Data Sources: National Vital Statistics System, CDC, and the U.S. Census Bureau.
Orthogonally linked

10. J Am Coll Cardiol. 2012;60:1715-21
Complex (interacting) biomarkers

11. Features of CAD Genetic Risk Variants
• Risk variants associated with
– Lipids (8)
– Hypertension (2)
– Independent of known risk factors (23)
• RR of each varies (6% to 92%); mean 18%.
• Population frequency varies (2% to 91%); mean
47%.
• Alleles/individual varies from 0 to 46; mean 17, and
range 7-37.
• Variants generally associated with risk of early CAD
• Most genetic risk variants for CAD are located in
non-coding DNA sequences

12. Cellular proteins belong to large, connected systems

14. Tests of the reno- and cardio-protection by
erythropoietin in CKD hypotheses: No benefit
Large biological systems generate unexpected (emergent) behavior when perturbed

15. J Biomed Biotechnol. 2011;2011:790132
Lewis GD et al. Metabolite profiling of blood from individuals undergoing
planned myocardial infarction reveals early markers of myocardial injury. J Clin
Invest. 2008 Oct;118(10):3503-12.

16. Gut flora metabolism of phosphatidylcholine promotes
cardiovascular disease: Linking biological systems
Nature 2011; 472:57-63.

17. Social Contagion in non-linear causal networks
N Engl J Med. 2007;357:370-9
Stat Med. 2013; 32:556-77

18. Evidence-based public health practice
• Social Networks and Childhood Obesity
• The Role of the Built Environment
• Interventions
– Targeting Existing Social Networks
– Purposeful Development of Social Networks
– Social Media: E-Mail and Texting Interventions
• Randomized Trials of Internet-Based Obesity Interventions
Circulation. 2013;127:260-7

19. Disease surveillance systems and T2 translation
Diabetes Care. 2000; 23:1794-8
Am. J. Epidemiol. 2010; 172: 517-524

20. Healthy People 2020: Reduce the proportion of
adults with high total blood cholesterol levels
Reduce the proportion of adults with high total
blood cholesterol levels
Baseline:
15.0 percent of adults aged 20 years
and older had total blood cholesterol
levels of 240 mg/dL or greater in 2005–
08 (age adjusted to the year 2000
standard population)
Target: 13.5 percent
Target-Setting Method: 10 percent improvement
Data Source:
National Health and Nutrition
Examination Survey (NHANES),
CDC/NCHS
More Information:
Data for this objective
The HP2010 objective with the same
definition was 12-14. View on
DATA2010

21. † A serum total cholesterol level greater than or equal to 240 mg/dL *Significant
decreasing trend (p<0.005). NOTE: HP 2010 = Healthy People 2010 Objective (17%).
Source: CDC/NCHS NHANES

23. Summary
• Successes and limitations of single risk
factor epidemiology
• Emerging interest in complex systems to
account for residual CHD risk
• New tools to study these relationships (GIS,
large biological and social databases, network
analysis, and surveillance systems)
• Comprehensive synthesis and application
remain a challenge for the future