Chapter 14Molecular and Genetic EpidemiologyLe.docx

Chapter 14
Molecular and Genetic
Epidemiology
Learning Objectives
• Differentiate between molecular and
genetic epidemiology
• Describe principles of inheritance and
sources of genetic variation
• Define epidemiologic approaches for
the identification of genetic
components to disease
Peeking into the “Black Box”
• Many risk factors can be quantified
through questionnaires, records, and

easily measured attributes (such as
blood pressure and anthropometrics).
• The biological mechanism(s) through
which these factors influence disease
is not always apparent (i.e., a “black
box”).
Value of Mechanistic Insight
• Biologic plausibility is a criterion for
causality.
• Linking lifestyle risk factors with
measures of biologic effect
strengthens interpretations of
causality.
• This linkage, in turn, provides
stronger support for interventions.
Why Distinguish Between

Molecular and Genetic
Epidemiology?
• The basic tenets and principles of
molecular and genetic epidemiology are
the same.
• However, there are specific features
regarding design, analysis and
interpretation inherent in the latter.
Definition of Genetic
Epidemiology
• A discipline that seeks to unravel
the role of genetic factors and their
interactions with environmental
factors in the etiology of diseases,
using family and population study
approaches.

Key Aspects of This Definition
• Inherited susceptibility does not mean
inherited disease--environment
matters!
• When families are studied, the
observations (study subjects) are no
longer independent.
• This dependence requires special
considerations for the analysis of
data.
Genetic Epidemiology is a
Method to Answer:
• Does a disease cluster in families?
• If so, is that clustering likely a result of shared
non-genetic risk factors?
• If the clustering is not accounted for by shared
lifestyle or common environment, is the pattern

of disease consistent with inherited effects?
• If so, where is the putative gene?
What Diseases or Risk Factors
Cluster in Families?
• Heart disease
• Various cancers
• Alcoholism
• Others
Epidemiologic Assessment of
Clustering
• Case-control study
• Comparison of the frequency of a
positive family history
• Expectation under genetic influence
Clustering of “Non-Genetic”

Exposures in Families
• Employment (e.g., several family
members with medical degrees)
• Radon from soil
• Religious preferences
• Lead in paint
• Others?
Major Point of This Section
• You cannot tell easily whether
clustering of a risk factor or disease
within a family is due to genetics,
culture, or shared environment
(including social or political factors).
• Clustering within a family will also
occur simply due to bad luck!
Other Correlates of Family

History
• Large family size
• Age of relatives (for an age-related
disease)
• Gender distribution (consider
testicular cancer, prostate disease,
ovarian cysts)
Analysis Approach
• Model Y (case/control status) =
established risk factors.
• Add family history variable to denote
“genetic” influence (i.e., share genes
with an individual who has the
outcome of interest).
Analysis Issues
• Try to compare (and control if necessary)

differences between cases and controls
with regard to size of family.
• Not easy to adjust for age of family
members or their risk factors.
• What types of data can you ask your
cases and controls to provide about their
relatives?
Motivation for Case-Control
Family Studies
• To rule out influence of shared
environment, family size differences, and
age on differences in the frequency of
family history between cases and
controls
• Need to enumerate the relatives of cases
and controls, and determine the disease
status and risk factor profile for each

relative
Conduct of Family Studies
• Ascertain “probands” (index cases).
• Define family (siblings? children?
parents? grandparents?)
• Invite family members to participate
• Collect data (and, typically, biological
samples)
How to Select Control Families
• Must decide how to identify controls
– From spouse’s side of proband’s family?
– Or select a random sample from the
population?
• Will controls be motivated to
participate?
• Must take HIPAA rules into account

Analysis Issues
• Exclude the index cases and controls
• Model disease (or behavior) of
interest based on age, sex, known
risk factors
• Evaluate evidence for genetic effect
through statistical significance of
variable(s) that indicate “relationship
to index case”
Analysis Issues (cont’d)
• Simplest “genetic” variable (1 if
relative of case, 0 if relative of control)
• Can also construct indicator variables
to designate type of relative (parent,
sibling, more distant relative)
• If not significant after including other

risk factors, then no evidence for
genetic influence
Evidence of Genetic Influence,
so far….
• Cases are more likely to have a family
history of disease than controls.
• The excess risk to relatives is not
accounted for by age, sex, and other risk
factors.
• What does that tell us about the
underlying genetic influence? (nothing)
Other Approaches to Identify
Genetic Influences
• Twin studies
• Segregation analysis
• Linkage analysis

Twin Studies
• A “natural experiment” of sorts
• Monozygotic (MZ) twins are genetically
identical.
• Dizygotic (DZ) twins share, on average,
the same proportion of genes as siblings.
• Greater concordance (for dichotomous
traits) or correlation (for continuous traits)
for MZ than DZ twins is evidence of a
genetic influence.
Linkage Analysis
• One way to distinguish cultural inheritance
from genetic inheritance is to track a
region of our DNA that is transmitted from
parents to offspring in the same manner
as the disease/outcome of interest.

• This procedure works well for diseases
that follow simple rules of inheritance
(e.g., autosomal dominant or recessive).
Segregation Analysis
• Historically, linkage analysis required
knowledge of the mode of
transmission of the putative gene
[dominant versus recessive, allele
frequency, lifetime or age-specific risk
(penetrance)].
• Segregation analysis has been used
to estimate these parameters.
Genetic Epidemiology of
Complex Diseases
• “Complex diseases” are ones for which
the genetic influence may be modest and

environmental factors contribute to
disease risk.
• Segregation analysis is not typically done
for “complex diseases.”
• Modern approaches ignore models of
inheritance (non-parametric methods).
Use of Epidemiology to
Understand Genetic Variation
• The methods of genetic epidemiology
have been applied historically to
identify genes.
• Typically, epidemiologists are not
interested in mapping genes, but
rather in figuring out how genes
interact with environment to influence
disease risk and outcome.

Molecular Epidemiology
• Related individuals are not necessarily required
for studies of the association of genetic
variation with risk of disease.
• Both cohort and case-control designs can be
used.
• Because genetic code (germline DNA) is
unchanged since conception, one readily can
employ retrospective designs.
Common Strategies for Genetic
Marker Selection
• Genome-wide approach with anonymous
DNA markers (1,000,000 SNPs on a chip)
• SNPs or simple tandem repeat markers in
“candidate” genes based on a priori
knowledge about presumed function
• SNPs in candidate genes with known

functional effect on level or activity of
protein product
Primer on Single Nucleotide
Polymorphisms (SNPs)
• Because of our redundant genetic code,
some SNPs will not alter the encoded
amino acid (e.g., GGA, GGG, GGT and
GGC all encode proline).
• SNPs that change an amino acid may not
necessarily lead to change in function of
transcribed protein.
More on SNPs
• SNPs that don’t change an amino acid
may still lead to alternate splicing of the
transcript (and therefore be functionally
important).

• SNPs in promoter region may influence
level of protein product–not activity (and
therefore be biologically significant).
• SNPs in non-coding regions may still have
functional effect.
Caveats About SNP Studies
• If you’re interested in gene x environment
interactions–best to focus on SNPs with known
functional effect.
• Human biology is complex: are alterations in
one component of a pathway compensated for
by another?
• Most SNPs are likely to be modest risk factors–
requiring large sample sizes to determine
statistically significant association.
Realistic Expectations

• Almost every gene is modified after translation
into protein (e.g., glycosylation, acetylation,
methylation).
• Thus, the correlation between DNA sequence
and protein is far from perfect.
• Most GWAS “hits” are in “gene deserts.”
• May be necessary to examine multiple SNPs
within a gene and several genes within a
pathway.
Molecular Epidemiology –
Beyond Genetics
• Biomarkers of exposure and disease
extend beyond DNA.
• Viral or bacterial load
• Morphometric analysis of tissues/cells
• Hormone or lipid levels in blood or
urine

• Other examples?
Conclusion
• Molecular and genetic epidemiology represent
specialty areas of expertise.
• These specialty areas utilize and apply
advances in molecular biology and molecular
genetics of disease to:
– Unravel disease etiology.
– Enable novel approaches for early detection.
– Inform more effective interventions by targeting
those at greatest risk.
Week 6 - Impacts of Big Data on Business Intelligence
This week we will explore how Big Data impacts Business
Intelligence.
This week's article provided a case study approach which
highlights how businesses have integrated Big Data Analytics
with their Business Intelligence to gain dominance within their
respective industry. Search the UC Library and/or Google
Scholar for a "Fortune 1000" company that has been successful
in this integration. Discuss the company, its approach to big

data analytics with business intelligence, what they are doing
right, what they are doing wrong, and how they can improve to
be more successful in the implementation and maintenance of
big data analytics with business intelligence.
Your paper should meet the following requirements:
• Be approximately 3-5 pages in length, not including the
required cover page and reference page.
• Follow APA guidelines. Your paper should include an
introduction, a body with fully developed content, and a
conclusion.
• Be clear with well-written, concise, using excellent grammar
and style techniques. You are being graded in part on the
quality of your writing.
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Chapter 13
Epidemiologic Aspects

of Work and the
Environment
Learning Objectives
• Define the term environmental
epidemiology
• Give examples of environmental agents
that are associated with human health
effects
• Provide examples of study designs used in
environmental epidemiology
• State methodologic difficulties with
research on environmental health effects
Environmental Epidemiology
• Study of disease and health
conditions (occurring in the
population) that are linked to
environmental factors
• Environmental exposures—outside
the control of the exposed individual

Two Examples of Environmental
Catastrophes
• Deepwater Horizon oil spill, Gulf of
Mexico, April 20 to July 15, 2010
• Fukushima nuclear reactor meltdown
following earthquake in Japan, March 11,
2011
Human Exposures to
Environmental Hazards
• Chemical agents
• Electromagnetic radiation
• Ionizing radiation
• Heavy metals
• Air pollution
• Temperature increases from global
warming and climate change

Health Effects Attributed to
Environmental Exposures
• Cancer
• Infertility
• Reproductive impacts
• Infectious diseases such as malaria
• Occupation-specific adverse
outcomes
Study Designs Used
• Descriptive study designs
– Helpful for setting priorities
– Hypothesis formulation
• Analytic study designs
– Effects of low-level exposures
– Exposure-effect relationships
– Retrospective cohort designs

Hazardous Agents in the Work
Environment
• Infectious agents
• Toxic substances
• Drugs
• Carcinogenic agents
Health Effects Associated with
Work Environment
• Health risks for pregnant workers and
the unborn fetus
• Various lung diseases
• Dermatologic problems
• Bladder cancer among dye workers
• Leukemia among workers exposed to
benzene

Study Designs Used in
Environmental Epidemiology
• Descriptive studies provide information
for setting priorities, identifying hazards,
and formulating hypotheses for new
occupational risks.
• Etiologic studies can be used to show
exposure-effect relationships.
Retrospective Cohort Studies
• Various end points are used to study
the effects of occupational exposures.
– Morbidity: self-reports of symptoms and
results of clinical examinations
– Mortality: comparison of mortality rates
of exposed workers with nonexposed
workers in the same industry

Collection of Exposure Data
• Employment records often are used
and may include:
– Personal identifiers to permit record
linkage
– Demographic characteristics
– Work history
– Information about potential confounding
variables, e.g., medical history, smoking
habits
The Healthy Worker Effect
• Observation that employed
populations tend to have a lower
mortality experience than the general
population.
• The healthy worker effect may reduce

the measure of effect for an exposure
that increases morbidity or mortality.
Ecologic Study Designs
• One use is the study of the health effects
of air pollution.
• Researchers measure the association
between average exposure to air pollution
within census tracts and the average
mortality in those census tracts.
• Unable to controI for individual factors,
e.g., smoking habits
Case-Control Studies
• Compared with cross-sectional
study designs, case-control studies
can provide more complete
exposure data.
• However, precise quantitation of
exposure and unobserved
confounding may be difficult to

achieve.
Toxicologic Concepts Related
to Environmental Epidemiology
• Dose-response
• Threshold
• Latency
• Synergism
Dose-Response Curve
• Graph that is used to assess the
effect of exposure to a chemical or
toxic substance upon an organism.
Threshold
• The lowest dose at which a
particular response may occur

Latency
• The time period between initial
exposure and a measurable response
• Latency can range from seconds
(acute toxic agents) to years
(mesothelioma).
• The long latency of health events in
environmental research makes the
detection of hazards difficult.
Synergism
• A situation in which the combined
effect of several exposures is greater
than the sum of the individual effects.
• Example: Study conducted among
asbestos insulation workers
demonstrated a synergistic
relationship between asbestos and
smoking in causing lung cancer.
Types of Agents
• Chemical agents

• Metallic compounds
• Electric and magnetic fields
• Allergens and molds
• Dusts
• Physical and mechanical energy
Chemical Agents
• Many types used at home and at
work
–Household cleaning agents
–Automotive chemicals
–Paints
–Pesticides
–Bisphenol A (BPA) in plastics
Chemical Agents (cont’d)
• Potential effects on human health

through acute toxicity, direct skin
irritation, contact dermatitis, or
long-term effects such as cancer
Pesticides: Used to Control
Pests
• Insecticides
• Herbicides
• Rodenticides
Four Classes of Insecticides
• Organophosphates
• Organocarbamates
• Pyrethroids
• Organochlorides
(organochlorines)
Organochloride Insecticides

• DDT
– Toxic to wildlife and persistent in
the environment
• Lindane
• Chlordane
Chemical Agents (cont’d)
• Asbestos
– Strictly speaking, a mineral fiber
– Was used commonly for ship
building, construction, insulation,
and automobiles
– Associated with asbestosis,
mesothelioma, and lung cancer
Metallic Compounds
• Arsenic
• Mercury
• Lead

Metallic Compounds (cont’d)
• Arsenic
– A crystalline metalloid
– Exists as inorganic compounds in the
environment
– Many uses
• Used as a preservative for residential
lumber outlawed
– Potential carcinogen, e.g., bladder
cancer
• Mercury
– Used for the treatment of syphilis, as an
agricultural fungicide, and in dental
amalgams
– Responsible for Minamata disease,
which occurred in the mid-1950s in
Minamata Bay, Japan
• A neurological condition linked to the

consumption of fish contaminated with
mercury
• Lead
– Once widely used in paint and gasoline
– Associated with serious central nervous
system effects even at low levels
– Has adverse effects on intelligence,
behavior, and development
– Between 1988 and 2002, percentage of
children with elevated blood lead levels
declined steeply
Electric and Magnetic Fields
• Sources include power lines, microwave
ovens, stoves, clocks, cellular phones.
• Los Angeles and Swedish studies found
an association between residential
proximity to power lines and childhood
cancer risk.

• U.S. and Norwegian studies found an
increased risk for male breast cancer
among male electrical workers.
Ionizing Radiation
• Consists of either particle energy
(e.g., highly energetic protons,
neutrons, and α and β particles) or
electromagnetic energy (e.g., γ-rays
and X-rays)
• Sources of ionizing radiation can be
natural or synthetic.
Ionizing Radiation (cont’d)
• Natural sources--examples are
radon and cosmic rays.
– Radon is one of the largest sources of
human exposure to ionizing radiation
and may be the cause of about 21,000
deaths from lung cancers in the U.S.
• Synthetic sources--examples are
medical x-rays and nuclear
generators.
Allergens and Molds

• Allergens--substances that provoke
an allergic reaction in susceptible
individuals
• Allergic reactions range from
dermatitis, asthma, and itchy eyes to
anaphylactic shock.
Physical and Mechanical
Energy
• Include agents associated with
unintentional injuries
• Unintentional injuries are a leading cause
of death within the age group 1-44 years
in the U.S.
• Also include such factors as noise,
vibration, and extremes of temperature
Global Warming

• Possible association with extreme
heat waves
• Climate changes in the eastern
U.S.
• Deaths associated with heat
waves
Monitoring and Surveillance of
Occupational Hazards
• Hazard surveillance--characterization of known
chemical, physical, and biologic agents in the
workplace
• Sentinel health event--a case of unnecessary
disease, unnecessary disability, or untimely
death whose occurrence is a warning signal
that the quality of preventive or medical care
may need to be improved

Environmental Hazards Found
in the Work Setting
• Biologic hazards--Hospital employees, sewage
workers, and agricultural workers may be
exposed to hazardous biologic agents. For
example, HIV may infect hospital workers
through accidental needle sticks.
• Mineral and organic dusts--Examples include
coal dust (mining and black lung disease) and
rubber dust (COPD).
Environmental Hazards Found
in the Work Setting (cont’d)
• Vapors and fumes are likely to become
increasing hazards due to the growing use
of chemical substances.
• Vapors--Include organic solvents such as
benzene, which may cause cancer and
damage internal organs (particularly the
liver)

Mineral and Organic Dusts
• Silicosis
• Pulmonary emphysema
• Chronic obstructive disease
• Coal workers’ pneumoconiosis
Industrial Chemicals
• Exposure in occupational settings
is up to 100 times higher than in
the ambient environment.
• Vinyl chloride—angiosarcoma of
the liver
• Pesticides
Noteworthy Community
Environmental Health Hazards
• Hazardous waste sites
• Air pollution

• Nuclear facilities
• Drinking water
Sick Building Syndrome
• Dryness of the skin and mucous
membranes
• Mental fatigue
• Headaches
• Symptoms diminish when affected
person leaves the building.
Hazardous Waste Sites
• Notorious sites in the U.S. include: Love
Canal, NY; Valley of the Drums, KY;
Times Beach, MO; Stringfellow acid pits,
CA; Casmalia Waste Disposal Facility, CA.
• Of great concern is the contamination of
water supplies by toxic wastes.
• Some possible adverse effects of
hazardous waste exposure include birth
defects, neurologic disease, and cancer.

Air Pollution
• Constituents of air pollution include sulfur
oxides, particles, ozone, and lead and
other heavy metals.
• Lethal air pollution episodes have
occurred worldwide.
• Studies conducted in New York City, St.
Louis, and Tennessee have shown a
correlation between increases in daily
mortality and increased air pollution.
Environmental Tobacco
Smoke (ETS)
• Nonsmokers who work in a smoking
environment have reduced pulmonary
function compared to nonsmokers in a
smoke-free work environment.
• ETS causes 3,000 lung cancer deaths
annually among nonsmokers.
• ETS is associated with children’s
bronchitis, pneumonia, and asthma.

Nuclear Facilities
• Include weapons production plants,
test sites, and nuclear power plants
• Studies of living in close proximity to
nuclear installations have shown
conflicting results regarding cancer
rates.
– Following the Chernobyl nuclear
power plant accident, thyroid cancer
rates increased near the reactor.
Drinking Water
• Chemical plants and nuclear facilities
may contaminate ground water.
• Chlorination of water supply has helped
to decrease the incidence of
gastroenteric diseases.
• Lead and asbestos particles may be
present in water and have potential for
toxicity.

Chapter 14Molecular and Genetic EpidemiologyLe.docx

Chapter 14Molecular and Genetic EpidemiologyLe.docx

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