Epidemiology matters: a new introduction to methodological foundations

Epidemiology matters: a new introduction to methodological foundations
What is a cause? Epidemiology matters: a new introduction to methodological foundations Chapter 7

Epidemiology Matters – Chapter 1
Seven steps Define the population of interest Conceptualize and create measures of exposures and health indicators Take a sample of the population Estimate measures of association between exposures and health indicators of interest Rigorously evaluate whether the association observed suggests a causal association Assess the evidence for causes working together Assess the extent to which the result matters, is externally valid, to other populations Epidemiology Matters – Chapter 1

Early conceptions of cause
“for now, I will stretch out mine hand, that I may smite thee and thy people with pestilence” God, from Exodus (9:14) Epidemiology matters – Chapter 7

Epidemiology matters – Chapter 7
A motivating example What is a cause? Disease causation – marble game Disease causation – time and space Public health implications Disease causation in a non-deterministic world Epidemiology and probability Summary Epidemiology 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? Epidemiology matters – Chapter 7

Unexposed Exposed Epidemiology matters – Chapter 7

Unexposed with disease Exposed with disease Unexposed Exposed Epidemiology matters – Chapter 7

Epidemiologists understand disease causation to be a multifactorial process Epidemiology 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? Epidemiology matters – Chapter 7

Would the depression have occurred if we kept everything about his life the same, but changed one detail? If everything about the man stayed the same, but the plant had not closed, would the depression have occurred? If everything about the man had stayed the same, but the divorce had not occurred, would the depression have occurred? If everything about the man had stayed the same, but his parents had more resources in his childhood, would the depression have occurred? Epidemiology 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. Epidemiology matters – Chapter 7

What is a cause? A motivating example What is a cause? Disease causation – marble game Disease causation – time and space Public health implications Disease causation in a non-deterministic world Epidemiology and probability Epidemiology matters – Chapter 7

Non-diseased Diseased Epidemiology matters – Chapter 7

Example: Individual diabetes
Combination 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 Take Type II diabetes, a multifactorial disease that is increasingly prevalent worldwide. There are many different combinations of types of causes that can bring about diabetes in a person. So, for example there are different marbles for smoking (a cause of this disease) and for obesity (also a cause of this disease). Epidemiology matters – Chapter 7

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. Take Type II diabetes, a multifactorial disease that is increasingly prevalent worldwide. There are many different combinations of types of causes that can bring about diabetes in a person. So, for example there are different marbles for smoking (a cause of this disease) and for obesity (also a cause of this disease). Epidemiology 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 Epidemiology matters – Chapter 7

Necessary and sufficient causes for populations
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 SG: Mention that unnecessary and insufficient causes are traditionally termed “risk factors” in the epidemiological and medical literature, but that this terminology is not precise enough for us. Epidemiology matters – Chapter 7

Necessary and sufficient causes Trisomy 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. Trisomy 21: All individuals with three copies of the 21st chromosome will evidence Down’s Syndrome (therefore, three copies of 21st chromosome is a sufficient cause). All individuals with Down’s syndrome have three copies of the 21st chromosome (therefore, three copies of 21st chromosome is a necessary cause) Epidemiology matters – Chapter 7

Necessary but insufficient causes Alcohol 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. Alcohol consumption: Not all individuals who consume alcohol will develop alcoholism (therefore, alcohol consumption is not a sufficient cause), but all individuals with alcoholism will have consumed alcohol (therefore, alcohol consumption is a necessary cause) Epidemiology matters – Chapter 7

Unnecessary but sufficient cause Hysterectomy 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. Hysterectomy: All women who have a hysterectomy are unable to become pregnant (therefore, hysterectomy is a sufficient cause to prevent pregnancy), but there are many other methods available to prevent pregnancy (therefore, hysterectomy is not a necessary cause) Epidemiology matters – Chapter 7

Unnecessary and insufficient cause Smoking 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. Smoking: Individuals who smoke are at higher risk for lung cancer. Not all individuals who smoke will develop lung cancer (therefore, smoking is not sufficient to cause lung cancer), and some people with lung cancer are lifelong nonsmokers (therefore, smoking is not necessary to cause lung cancer). Epidemiology matters – Chapter 7

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 Epidemiology matters – Chapter 7

Collecting marbles across the life course: Example
Infancy Childhood Adolescence Adulthood ] Collecting throughout life tobacco smoke in utero chronic poverty, chaotic home environment in childhood cigarette smoking starts in adolescence poor nutrition in adulthood . We have one individual progressing through the life course, from birth, to adolescence, to young adulthood, to older adulthood. Some marbles are present at birth, some are acquired at one point, and some slowly accumulate. For example, this person had one marble prior to birth (the black marble at the top of Figure 2). This marble may represent exposure to tobacco smoke or other toxins in utero. He also acquired a series of grey marbles in childhood. These may represent ongoing exposures to, for example, chronic poverty, chaotic home environment, or low levels of paternal support. In adolescence, he began being exposed to the white marble, which accumulated yearly, with increasing amounts of exposure during adulthood. This might represent cigarette smoking, which begins for this individual in adolescence in a low dose, and then increases in adulthood and remains a consistent exposure throughout his life. Additional marbles began accumulating during adulthood, until disease onset at the bottom of Figure 2. Epidemiology matters – Chapter 7

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 Example: When infectious diseases are transmitted between people (e.g., through salivary or skin-to-skin spread, genital contact, or from mother to child), one person’s disease status becomes an exposure for those who are in direct contact with that person Epidemiology matters – Chapter 7

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 Epidemiology matters – Chapter 7

Sharing marble exposures
Person 2 Person 1 Person 3 Person 4 Start with 4 people and their individual set of marbles Epidemiology matters – Chapter 7

Sharing marble exposures
Person 2 Person 1 Person 3 Person 4 Each marble represents an exposure. Marbles with the same color and pattern are varying amounts of the same exposure. Some marbles are shared between individuals (for example, Person 1 and Person 3 share four clear marbles, and Person 3 shares one grey marble with Person 4. Individuals also have marbles that are unique and unshared; for example Person 1 has two black marbles that are unshared, as does Person 4. Examples of shared marbles could be neighborhoods, social norms, or sex partners. Examples of unique marbles could be genetic alleles, dietary patterns, and experiences of personal trauma. Epidemiology matters – Chapter 7

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

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

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 individuals Epidemiology matters – Chapter 7

Public health target? Exposure combinations and disease causation Which cause should we try and prevent? Epidemiology matters – Chapter 7

Public health target? Remove cause W Person 1 and 3 saved X Person 1 and 2 saved Y Person 1, 2, and 3 saved Z Person 2 and 3 saved Target cause Y for prevention to save most people Epidemiology 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 Population level: causes may be necessary and/or sufficient, but need not be either Multifactorial and complex diseases often caused many factors necessary in at least 1 person Causes may be unnecessary (not all individuals with the disease were exposed to the factor) and insufficient (not everyone exposed develops the disease) Epidemiology 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 We now understand the following: the process of disease development may begin in utero and continue until the moment that the disease occurs. Often many causes have to align in order for a disease to occur in an individual. Smoking is not sufficient to cause lung cancer; smoking must act in concert with other causes. Perhaps an individual smokes, works in a occupation with a high degree of exposure to asbestos (Saracci 1977) or has a genetic predisposition to develop lung cancer (Takahashi, Nau et al. 1989). Furthermore, another person who develops the same disease may have a different constellation of causes. One person’s heart disease may involve a diet high in saturated fat, whereas another person’s heart disease may not. Causes can be shared across people or unique to a certain person. The idea that many causes must accumulate together 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, than all of these marbles interact with each other. By preventing exposure to even one marble, the disease will not occur. Epidemiology 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 We now understand the following: the process of disease development may begin in utero and continue until the moment that the disease occurs. Often many causes have to align together in order for a disease to occur in an individual. Smoking is not sufficient to cause lung cancer; smoking must act in concert with other causes. Perhaps an individual smokes, works in a occupation with a high degree of exposure to asbestos (Saracci 1977) or has a genetic predisposition to develop lung cancer (Takahashi, Nau et al. 1989). Furthermore, another person who develops the same disease may have a different constellation of causes. One person’s heart disease may involve a diet high in saturated fat, whereas another person’s heart disease may not. Causes can be shared across people or unique to a certain person. The idea that many causes must accumulate together 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, than all of these marbles interact with each other. By preventing exposure to even one marble, the disease will not occur. Epidemiology 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 We now understand the following: the process of disease development may begin in utero and continue until the moment that the disease occurs. Often many causes have to align together in order for a disease to occur in an individual. Smoking is not sufficient to cause lung cancer; smoking must act in concert with other causes. Perhaps an individual smokes, works in a occupation with a high degree of exposure to asbestos (Saracci 1977) or has a genetic predisposition to develop lung cancer (Takahashi, Nau et al. 1989). Furthermore, another person who develops the same disease may have a different constellation of causes. One person’s heart disease may involve a diet high in saturated fat, whereas another person’s heart disease may not. Causes can be shared across people or unique to a certain person. The idea that many causes must accumulate together 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, than all of these marbles interact with each other. By preventing exposure to even one marble, the disease will not occur. Epidemiology 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? Phenylketonuria (PKU) is a rare disorder present at birth characterized by the inability to process a certain amino acid, phenylalanine. The disorder, when untreated, results in mental retardation, altered appearance (light skin and hair), seizures and hyperactivity, among other symptoms. The necessary cause for PKU is inheriting a particular genetic sequence from both mother and father. However, this inherited genetic sequence will not result in the expressed phenotype unless an individual eats a diet rich in phenylalanine. Therefore a diet rich in phenylalanine is also necessary for the symptoms of PKU to manifest. What type of cause is genetic sequence? - Necessary, insufficient What type of a cause is diet? - Necessary, insufficient Epidemiology 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? Phenylketonuria (PKU) is a rare disorder present at birth characterized by the inability to process a certain amino acid, phenylalanine. The disorder, when untreated, results in mental retardation, altered appearance (light skin and hair), seizures and hyperactivity, among other symptoms. The necessary cause for PKU is inheriting a particular genetic sequence from both mother and father. However, this inherited genetic sequence will not result in the expressed phenotype unless an individual eats a diet rich in phenylalanine. Therefore a diet rich in phenylalanine is also necessary for the symptoms of PKU to manifest. What type of cause is genetic sequence? - Necessary, insufficient What type of a cause is diet? - Necessary, insufficient Epidemiology matters – Chapter 7

Diet and phenylketonuria (PKU)
Only genetic + PA-rich diet = PKU manifestation Phenylketonuria (PKU) is a rare disorder present at birth characterized by the inability to process a certain amino acid, phenylalanine. The disorder, when untreated, results in mental retardation, altered appearance (light skin and hair), seizures and hyperactivity, among other symptoms. The necessary cause for PKU is inheriting a particular genetic sequence from both mother and father. However, this inherited genetic sequence will not result in the expressed phenotype unless an individual eats a diet rich in phenylalanine. Therefore a diet rich in phenylalanine is also necessary for the symptoms of PKU to manifest. Epidemiology matters – Chapter 7

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 The global epidemic of obesity continues to move to the forefront of global public health priorities. Obesity is a complex health outcome with causes throughout the life course at many levels of organization. For example, there is considerable interest in identifying genetic variants that are involved in the process of increasing and maintaining high weight (Bell, Walley et al. 2005). Further, studies have begun to address the impact of the in utero environment on obesity in childhood and adulthood (Ravelli, Stein et al. 1976). Factors in childhood such as food insecurity, socio-economic position, and contextual factors such as availability of healthy food and food cost are also implicated in the obesity epidemic (Adams, Grummer-Strawn et al. 2003). Among both children and adults, health behaviors are also central causes of obesity (Ludwig, Peterson et al. 2001). That is, individuals who consume high-sugar, low nutrient foods such as sugar sweetened beverages (SSBs) are at high risk for weight gain and potentially obesity (Ludwig, Peterson et al. 2001). However, consumption of SSBs alone is not sufficient to cause obesity. The combination of high SSB consumption, low amounts of physical activity, and perhaps genetic predisposition that regulates the body’s ability to metabolize sugar may all work together to cause obesity. Given that there is no “one cause” of obesity, understanding obesity requires us to conceptualize many causes interacting together to result in each obesity case. Epidemiology matters – Chapter 7

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 The global epidemic of obesity continues to move to the forefront of global public health priorities. Obesity is a complex health outcome with causes throughout the life course at many levels of organization. For example, there is considerable interest in identifying genetic variants that are involved in the process of increasing and maintaining high weight (Bell, Walley et al. 2005). Further, studies have begun to address the impact of the in utero environment on obesity in childhood and adulthood (Ravelli, Stein et al. 1976). Factors in childhood such as food insecurity, socio-economic position, and contextual factors such as availability of healthy food and food cost are also implicated in the obesity epidemic (Adams, Grummer-Strawn et al. 2003). Among both children and adults, health behaviors are also central causes of obesity (Ludwig, Peterson et al. 2001). That is, individuals who consume high-sugar, low nutrient foods such as sugar sweetened beverages (SSBs) are at high risk for weight gain and potentially obesity (Ludwig, Peterson et al. 2001). However, consumption of SSBs alone is not sufficient to cause obesity. The combination of high SSB consumption, low amounts of physical activity, and perhaps genetic predisposition that regulates the body’s ability to metabolize sugar may all work together to cause obesity. Given that there is no “one cause” of obesity, understanding obesity requires us to conceptualize many causes interacting together to result in each obesity case. Epidemiology matters – Chapter 7

Summary: Causation in nondeterministic world
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 Population level: causes may be necessary and/or sufficient, but need not be either Multifactorial and complex diseases often caused many factors necessary in at least 1 person Causes may be unnecessary (not all individuals with the disease were exposed to the factor) and insufficient (not everyone exposed develops the disease) Epidemiology 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: and accessed on 9/10/2013 Epidemiology matters – Chapter 7

Hypothetical example X,Y, Z Reality
X, Y, and Z are all necessary and insufficient causes of disease in an individual Component Causes # People with component causes Probability of disease X Y Z ✔ 10 1 8 11 5 9 3 12 42 Questions: What is the probability of disease for individuals with component causes x,y, and z? How many people have a 0 probability of disease? Epidemiology matters – Chapter 7

Hypothetical example X,Y, Z
Reality Measured Component Causes # People with component causes Probability of disease X Y Z ✔ 10 1 8 11 5 9 3 12 42 Component Causes # People with component causes Probability of disease X Y Z ✔ 10 1 8 11 5 9 3 12 42 X, Y, and Z are all necessary and insufficient causes of disease What is prevalence of disease, given exposure to X? N exposed to X = 38 ( ) N exposed to X with disease = 10 Prevalence of disease : P(D|X)=10/38 = 0.26 X, Y, and Z are all necessary and insufficient causes of disease in an individual What is prevalence of disease, given exposure to X? N exposed to X = 38 ( ) N exposed to X with disease = 10 Prevalence of disease : P(D|X)=10/38 = 0.26 Epidemiology matters – Chapter 7

Transition from knowing all component causes to just those measured takes epidemiologist from deterministic to probabilistic Epidemiology matters – Chapter 7

Hypothetical example A,B,C, X,Y, Z Reality
A,B, and C OR X, Y, and Z are all necessary and insufficient causes of disease in an individual Component Causes # People with component causes Probability of disease A B C X Y Z ✔ 5 1 6 10 20 15 14 12 18 Questions: What is the probability of disease for individuals with 1st component causes? How many people have a 0 probability of disease? 79 Epidemiology matters – Chapter 7

Hypothetical example A,B,C, X,Y, Z
Reality Measured Component Causes # People with component causes Probability of disease A B C X Y Z ✔ 5 1 6 10 20 15 14 12 18 Component Causes # People with component causes Probability of disease A B C X Y Z ✔ 5 1 6 10 20 15 14 12 18 Questions: What is the probability of disease for individuals with 1st component causes? How many people have a 0 probability of disease? 79 Probabilistic – not deterministic A,B, and C OR X, Y, and Z are all necessary and insufficient causes of disease in an individual What is probability of disease, given X? P(D|X): 15/47, or 0.32 or 32% Epidemiology matters – Chapter 7

Remember this? Unaffected with disease Affected with disease Unexposed

Probabilistic or deterministic?
Higher ‘risk’ of disease given exposure to X Probabilistic or deterministic? Epidemiology matters – Chapter 7

Disease causation is a multifactorial process A cause, necessary or sufficient Disease causation, the marble game Disease causation, time and space Public health implications, identifying component causes for most individuals Disease causation in a non-deterministic world - interaction Epidemiology is probabilistic Summary Epidemiology matters – Chapter 7

Seven steps Define the population of interest Conceptualize and create measures of exposures and health indicators Take a sample of the population Estimate measures of association between exposures and health indicators of interest Rigorously evaluate whether the association observed suggests a causal association Assess the evidence for causes working together Assess the extent to which the result matters, is externally valid, to other populations Epidemiology Matters – Chapter 1

epidemiologymatters.org Epidemiology Matters – Chapter 1

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