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What is a cause?
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What is a cause?
Epidemiology matters: a new introduction to methodological foundationsChapter 7
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2Epidemiology Matters – Chapter 1
Seven steps
1. Define the population of interest2. Conceptualize and create measures of exposures and health
indicators3. Take a sample of the population4. Estimate measures of association between exposures and health
indicators of interest
5. Rigorously evaluate whether the association observed suggests a causal association
6. Assess the evidence for causes working together7. Assess the extent to which the result matters, is externally valid, to
other populations
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Epidemiology matters – Chapter 7 3
“for now, I will stretch out mine hand, that I may smite thee and thy people with pestilence”
God, from Exodus (9:14)
Early conceptions of cause
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4Epidemiology matters – Chapter 7
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
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5Epidemiology matters – Chapter 7
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
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6Epidemiology matters – Chapter 7
Motivating examples The Uncle Joe example “My mother smoked in pregnancy - no one knew the
health dangers back then - and I’m just fine. All of these warnings about smoking during pregnancy are overdone.”
If one person smoked in pregnancy with no adverse consequences for their offspring, can we conclude that smoking in pregnancy is not harmful?
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Epidemiology matters – Chapter 7 7
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ExposedUnexposed
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ExposedUnexposed Unexposed with disease
Exposed with disease
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10Epidemiology matters – Chapter 7
Epidemiologists understand disease causationto be a multifactorial process
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11Epidemiology matters – Chapter 7
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
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12Epidemiology matters – Chapter 7
Example: A man’s depression
Man developed depression Personal history:
Born Boise, Idaho 1965 Parents working class Youngest of 5 children Trouble with the law growing up Married at 25, divorced 4 years ago Lost job 2 years ago
What are the causes of the man’s depression?
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13Epidemiology matters – Chapter 7
Would the depression have occurred if we kept everything about his life the same, but changed one detail?
1. If everything about the man stayed the same, but the plant had not closed, would the depression have occurred?
2. If everything about the man had stayed the same, but the divorce had not occurred, would the depression have occurred?
3. If everything about the man had stayed the same, but his parents had more resources in his childhood, would the depression have occurred?
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14Epidemiology matters – Chapter 7
Counterfactual
The counterfactual is the condition that is counter to the fact
A factor is a cause if the outcome would not have occurred in the absence of that factor, holding all other things constant, including space and time.
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15Epidemiology matters – Chapter 7
What is a cause?
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
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16Epidemiology matters – Chapter 7
Non-diseased Diseased
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Example: Individual diabetesCombination of causes in individuals
Person 1. Obese weight, lack of preventive care, diabetes family history, 20 pack-years smoking
Person 2. Poor nutritional education, diabetes family history, high blood pressure, advanced age
Person 3. Obese weight, diabetes family history, high blood pressure
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Epidemiology matters – Chapter 7 18
Example: Individual diabetes
Is each factor necessary? Is each factor sufficient?
For each individual case, all component causes are necessary for that individual, but none are sufficient.
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19Epidemiology matters – Chapter 7
Causes and the individual marble game
Each marble is a component cause But, one marble is rarely sufficient to cause disease A particular marble set can be a sufficient cause for disease There can be more than one marble set that become a
sufficient cause Causes are rooted in a counterfactual definition, each
marble is a necessary cause of disease for that particular sufficient cause set
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20Epidemiology matters – Chapter 7
Necessary if all cases of disease require the cause in order for disease to onset
Sufficient if all individuals exposed to the cause will acquire the disease
Causes can be necessary and sufficient unnecessary but sufficient necessary but insufficient unnecessary and insufficient
Necessary and sufficient causes for populations
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Epidemiology matters – Chapter 7
Necessary and sufficient causesTrisomy 21 and Down Syndrome
All individuals with three copies of the 21st chromosome will evidence Down Syndrome. Trisomy 21 is thus sufficient for DS.All individuals with Down syndrome have three copies of the 21st chromosome. Trisomy 21 is thus necessary for DS.
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Epidemiology matters – Chapter 7
Necessary but insufficient causesAlcohol consumption and alcoholism
Not all individuals who consume alcohol will develop alcoholism. Alcohol consumption is thus insufficient for alcoholism.However, all individuals with alcoholism will have consumed alcohol. Alcohol consumption is thus necessary for alcoholism.
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Unnecessary but sufficient causeHysterectomy and pregnancy prevention
All women who have a hysterectomy are unable to become pregnant. Hysterectomy is thus sufficient for pregnancy prevention.Not all pregnancies are prevented through hysterectomy. Hysterectomy is thus unnecessary for pregnancy prevention.
23Epidemiology matters – Chapter 7
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Unnecessary and insufficient causeSmoking and lung cancer
Not all individuals who smoke will develop lung cancer. Smoking is thus insufficient to cause lung cancer.Not all lung cancer cases are smokers. Smoking is thus unnecessary to cause lung cancer.
24Epidemiology matters – Chapter 7
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25
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
Epidemiology matters – Chapter 7
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Collecting marbles across the life course
People can accumulate marbles At birth In adolescence During young adulthood At older adulthood At one point vs. slow accumulation over time
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Collecting marbles across the life course: Example
Collecting throughout life tobacco smoke in utero chronic poverty, chaotic
home environment in childhood
cigarette smoking starts in adolescence
poor nutrition in adulthood
Infancy
Childhood
Adolescence
Adulthood]
27Epidemiology matters – Chapter 7
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Marbles are not independent
Shared across individuals One person’s marble collection may influence
another person’s marble collection Example, person-to-person infectious disease
transmission
Epidemiology matters – Chapter 7
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Examples of shared marbles
Unhealthy food environment Community violence Social norms around substance use and cigarette
smoking; e.g., adolescents are more likely to begin smoking if an influential peer begins smoking
Policies and laws managing access to quality health care
29Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
30Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
31Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
32Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
33Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
Epidemiology matters – Chapter 7
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Person 1 Person 2
Person 3 Person 4
Sharing marble exposures
Epidemiology matters – Chapter 7
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Summary: marble analogy
Individuals share marbles and transmit marbles from one space to another
Within each person’s space, there remains a complete set of marbles that is necessary to cause disease.
One person’s complete set of marbles may differ from another persons
Epidemiology matters – Chapter 7
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Summary: causes in time and space At population level need to understand exposure to
unhealthy environments and transmission of disease to understand and intervene to prevent adverse health conditions
By identifying marbles that are common across many marble spaces, we can identify the exposures and environments for intervention and prevention efforts.
Epidemiology matters – Chapter 7
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38
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
Epidemiology matters – Chapter 7
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Public health implications Marble example, individual
Each individual’s set of marbles that caused disease may be unique, with or without overlap across individuals
Each marble was necessary for that person to develop the disease when and how he or she did
Marble example, population Epidemiologists look for the ‘marbles’ that are most common across
individuals with disease compared to those without disease Preventing any one of the marbles can prevent disease in that
individual Prevent common marbles can prevent more disease in more
individualsEpidemiology matters – Chapter 7
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Exposure combinations and disease causation
Public health target?
Which cause should we try and prevent?Epidemiology matters – Chapter 7
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Public health target?
Remove causeW
Person 1 and 3 savedX
Person 1 and 2 savedY
Person 1, 2, and 3 savedZ
Person 2 and 3 savedTarget cause Y for prevention to save most people
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42Epidemiology matters – Chapter 7
Summary: public health implications
At the population level causes may be necessary and/or sufficient, but need not be either
Multifactorial and complex diseases are often caused by many factors necessary in at least one person
Identifying factors, i.e., component causes, common to most individuals has the greatest impact on reducing disease for largest amount of people
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43Epidemiology matters – Chapter 7
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
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44Epidemiology matters – Chapter 7
From marble space to probability Process of disease development may begin in utero
and continue until the moment that the disease occurs
Often many causes must align for a disease to occur in an individual
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45Epidemiology matters – Chapter 7
Example: Smoking and lung cancer Smoking is not sufficient to cause lung cancer; smoking
must act with other causes – i.e. an individual smokes, works in a occupation with a high degree of exposure to asbestos, has a genetic predisposition to develop lung cancer
Another person who develops lung cancer may have a different constellation of causes
Causes can be shared across people or be unique to a certain person
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46Epidemiology matters – Chapter 7
From marble space to probability
The idea that many causes must accumulate through the life course before the disease manifests is, in epidemiology, expressed as the concept of interaction
That is, if seven marbles are all necessary to cause disease in an individual, then all of these marbles interact with each other
By preventing exposure to even one marble, the disease will not occur
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47Epidemiology matters – Chapter 7
Example A. Diet and phenylketonuria (PKU)
Disorder: PKU, an inability to process phenylalanine (amino acid); if untreated results in altered appearance, hyperactivity, mental retardation, and seizures
All PKU patients have specific maternal and paternal genetic sequence alone will not cause PKU
What type of cause is genetic sequence?
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48Epidemiology matters – Chapter 7
Diet and phenylketonuria (PKU)
Disorder: PKU, an inability to process phenylalanine (amino acid); if untreated results in altered appearance, hyperactivity, mental retardation, and seizures
All PKU patients have specific maternal and paternal genetic sequence alone will not cause PKU
What type of cause is a PA-rich diet?
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49Epidemiology matters – Chapter 7
Diet and phenylketonuria (PKU)
Only genetic + PA-rich diet
= PKU manifestation
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Example B. Causes of obesity
Genetic variants involved in the process of increasing and maintaining high weight
In utero environment on obesity in childhood and adulthood
Childhood factors including food insecurity, socio-economic position, availability of healthy food and food cost
Health behaviors including high consumption of sugar-sweetened beverages
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Example B. Causes of obesity
Potential causal mechanism may be
High consumption of sugar sweetened beverages + low physical activity + genetic predisposition = obesity
There is no single cause of obesity, we need to conceptualize causes as interacting
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52Epidemiology matters – Chapter 7
Interaction: many causes must accumulate through the life course before the disease manifests
Necessary but insufficient causes interact for disease to manifest in an individual
Multifaceted disease causation requires many component causes interacting
Summary: Causation in nondeterministic world
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53Epidemiology matters – Chapter 7
1. A motivating example
2. What is a cause?
3. Disease causation – marble game
4. Disease causation – time and space
5. Public health implications
6. Disease causation in a non-deterministic world
7. Epidemiology and probability
8. Summary
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54Epidemiology matters – Chapter 7
Epidemiology is probabilistic
Deterministic “… occurrences … are causally determined by preceding events or natural laws”*
Probabilistic “of, relating to, or based on probability”*
Epidemiology is probabilistic Considering component causes Often have not identified all of the causal partners for a
sufficient cause
*Definitions: http://www.merriam-webster.com/dictionary/determinism and http://www.merriam-webster.com/dictionary/probabilistic accessed on 9/10/2013
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55Epidemiology matters – Chapter 7
Hypothetical example X,Y, ZReality
Component Causes # People with component causes Probability of disease
X Y Z
✔ ✔ ✔ 10 1
✔ ✔ 8 0
✔ ✔ 11 0
✔ ✔ 5 0
✔ 9 0
✔ 3 0
✔ 12 0
42 0
X, Y, and Z are all necessary and insufficient causes of disease in an individual
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56Epidemiology matters – Chapter 7
Hypothetical example X,Y, Z
Component Causes
# People with component causes
Probability of disease
X Y Z
✔ ✔ ✔ 10 1
✔ ✔ 8 0
✔ ✔ 11 0
✔ ✔ 5 0
✔ 9 0
✔ 3 0
✔ 12 0
42 0
X, Y, and Z are all necessary and insufficient causes of disease in an individualWhat is prevalence of disease, given exposure to X?N exposed to X = 38 (10+8+11+9)N exposed to X with disease = 10Prevalence of disease : P(D|X)=10/38 = 0.26
Component Causes
# People with component causes
Probability of disease
X Y Z
✔ 10 1
✔ 8 0
✔ 11 0
5 0
✔ 9 0
3 0
12 0
42 0
RealityMeasured
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Epidemiology matters – Chapter 7 57
Transition from knowing all component causes to just those measured takes epidemiologist from
deterministic to probabilistic
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58Epidemiology matters – Chapter 7
Hypothetical example A,B,C, X,Y, ZReality
Component Causes # People with component causes
Probability of disease
A B C X Y Z
✔ ✔ ✔ ✔ ✔ ✔ 5 1
✔ ✔ ✔ 6 1
✔ ✔ ✔ 10 1
✔ ✔ 20 0
✔ ✔ 15 0
✔ ✔ 14 0
✔ ✔ 12 0
✔ ✔ ✔ ✔ 18 0
A,B, and C OR X, Y, and Z are all necessary and insufficient causes of disease in an individual
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59Epidemiology matters – Chapter 7
Hypothetical example A,B,C, X,Y, Z
Component Causes # People with component causes
Probability of disease
A B C X Y Z
✔ ✔ ✔ ✔ ✔ ✔ 5 1
✔ ✔ ✔ 6 1
✔ ✔ ✔ 10 1
✔ ✔ 20 0
✔ ✔ 15 0
✔ ✔ 14 0
✔ ✔ 12 0
✔ ✔ ✔ ✔ 18 0
RealityMeasured
A,B, and C OR X, Y, and Z are all necessary and insufficient causes of disease in an individualWhat is probability of disease, given X?P(D|X): 15/47, or 0.32 or 32%
Component Causes # People with component causes
Probability of disease
A B C X Y Z
✔ 5 1
6 1
✔ 10 1
✔ 20 0
15 0
14 0
✔ 12 0
18 0
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ExposedUnexposed Unaffected with disease
Affected with disease
Remember this?
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Higher ‘risk’ of disease given exposure to X
Probabilistic or deterministic?
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62Epidemiology matters – Chapter 7
1. Disease causation is a multifactorial process
2. A cause, necessary or sufficient
3. Disease causation, the marble game
4. Disease causation, time and space
5. Public health implications, identifying component causes for most individuals
6. Disease causation in a non-deterministic world - interaction
7. Epidemiology is probabilistic
8. Summary
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63Epidemiology Matters – Chapter 1
Seven steps
1. Define the population of interest2. Conceptualize and create measures of exposures and health
indicators3. Take a sample of the population4. Estimate measures of association between exposures and health
indicators of interest
5. Rigorously evaluate whether the association observed suggests a causal association
6. Assess the evidence for causes working together7. Assess the extent to which the result matters, is externally valid, to
other populations
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64Epidemiology Matters – Chapter 1
epidemiologymatters.org