1. The Epidemiologic Approach to Causation

2. What is a Cause?
Merriam-Webster Dictionary: Something that brings about a result especially a person or thing that is the agent of bringing something about.
KJ Rothman: An event, condition, or characteristic without which the disease would not have occurred.
M Susser: Something that makes a difference.

3. What is a Cause?

4. Problem How do we know when something makes a difference?
Association is not equal to causation.
Consider the following statement: If the rooster crows at the break of dawn, then the rooster caused the sun to rise.

6. Characteristics of a cause
Must precede the effect (proximate vs. distant)
Can be either host or environmental factors
Characteristics, conditions
actions of individuals
events, natural, social or economic phenomena
Positive (presence of a causative exposure) or negative (lack of a preventive exposure)

8. Terminology: Causes vs. Risk Factors Which are the following?
Characteristics
High Risk Group for Breast Cancer
Low Risk Group for Breast Cancer
Country of Birth
North America, Northern Europe
Asia, Africa
Socioeconomic Status
High
Low
Marital Status
Never married
Ever Married

9. What are some of the causes of the following diseases and events?
Influenza:
Lung Cancer:
Breast Cancer:
Automobile Fatality:

10. Historical Development of Theories of Causation
Divine retribution; imbalance in body humors caused by air, water, land, stars; spontaneous generation
Miasma: Disease transmitted by miasmas or clouds clinging to earth’s surface
Germ Theory of Disease and Henle-Koch Postulates: Most important postulate is that the microorganism must always be found with the disease. This postulate embodies the idea of specificity of a cause. That is, a one to one relationship between an exposure and a disease.

11. Historical Development of Theories of Causation
Web of Causation: A paradigm for the causes of chronic diseases. Most important shift from Henle-Koch Postulates is the idea of multiple causes. Postulates were also revised for establishing causation in chronic diseases.
Recent Controversies
Causation cannot be established.
Causal criteria should be abandoned. Has anyone seen the spider that produced the web?

15. General Model of Causation (Causal Pies) by KJ Rothman
Sufficient cause: A set of conditions without any one of which the disease would not have occurred. (This is one whole pie.)
Component cause: Any one of the set of conditions which are necessary for the completion of a sufficient cause. (This is a piece of the pie.)
Necessary cause: A component cause that is a member of every sufficient cause.

17. Attributes of the Causal Pie
Completion of a sufficient cause is synonymous with occurrence (although not necessarily diagnosis) of disease.
Component causes can act far apart in time.
A component cause can involve the presence of a causative exposure or the lack of a preventive exposure.
Blocking the action of any component cause prevents the completion of the sufficient cause and therefore prevents the disease by that pathway.

23. Causal “Guidelines" Suggested by Sir AB Hill (1965)
Strength of the association; Consistency; Specificity; Temporality; Biological gradient; Plausibility; Coherence; Experiment; Analogy
Purpose: Guidelines to help determine if associations are causal.
Should not be used as rigid criteria.
Hill even stated that he did not intend for these "viewpoints" to be used as “hard and fast rules.”

24. 1. Strength of the association
The larger the association, the more likely the exposure is causing the disease.
Example:
Smoking  Lung Cancer RR = 9
Heavy Smoking  Lung Cancer RR = 20
Strong associations are more likely to be causal because they are unlikely to be due entirely to bias and confounding.
Weak associations may be causal but it is harder to rule out bias and confounding.

25. 2. Consistency
The association is observed repeatedly in different persons, places, times, and circumstances.
Replicating the association:
different samples
different study designs
different investigators
Smoking  Lung cancer
29 retrospective and 7 prospective studies
There are good reasons why study results may differ.
low versus high level exposures

26. 3. Specificity A single exposure should cause a single disease.
Stems from infectious diseases
Not really true for non-infectious diseases
When present, specificity does provide evidence of causality, but its absence does not preclude causation.

27. 4. Temporality Causal factor must precede the disease in time.
This is the only one of Hill's criteria that everyone agrees with.
Prospective studies do a good job establishing the correct temporal relationship between an exposure and a disease.
Smoking at baseline  incident cancer

28. 5. Biological Gradient
A “dose-response” relationship between exposure and disease. Persons who have increasingly higher exposure levels have increasingly higher risks of disease.
Pack Years Smoked  Death from Lung Cancer
Biology
Dose-response
Threshold effect

29. 6/7. Plausibility/Coherence
Biological or social model exists to explain the association.
Association does not conflict with current knowledge of natural history and biology of disease.
Cigarettes contain many carcinogenic substances.
Many epidemiologic studies have identified cause-effect relationships before biological mechanisms were identified.
carcinogenic substances in cigarette smoke were discovered after the initial epidemiologic studies

30. 8. Experiment
Investigator-initiated intervention that modifies the exposure through prevention, treatment, or removal should result in less disease.
Smoking cessation programs  ↓Lung Cancer
Provides strong evidence for causation, but most epidemiologic studies are observational.

31. 9. Analogy
Has a similar relationship been observed with another exposure and/ or disease?
Example: Effects of Thalidomide and Rubella on the fetus provide analogy for effects of similar substances on the fetus.

32. In summary, Sir Bradford Hill's “guidelines" are useful guides for:
Remembering distinctions between association and causation in epidemiologic research
Critically reading epidemiologic studies
Designing epidemiologic studies
Interpreting the results of your own study

33. Temporality
Was temporal relationship established in the article examining the association between artificial sweeteners and obesity.

34. Strength and Dose Response

35. Consistency

36. Biologic Plausibility
There may be no causal relationship between AS use and weight gain. Individuals seeking to lose weight often switch to ASs in order to reduce their caloric intake. AS use might therefore simply be a marker for individuals already on weight-gain trajectories, which continued despite their switching to ASs. This is the most obvious possible explanation of our findings. Increased fast food consumption among soda users might further confound apparent associations (24).
Do consumers of “lite” products overestimate caloric savings achieved through AS use, and unintentionally overcompensate elsewhere in their diets?
Because sucrose partially counteracts decreased resting metabolic rate in low-calorie dieters(39), sugar avoiders might face metabolic-rate disadvantages. This might explain the apparently paradoxical findings of increased ΔBMI among AS users, despite lower baseline caloric intake, as in our own study, and/or apparently healthier food choices, as reported in the American Cancer Society study (16).
Finally, aspartame, acesulfame potassium, saccharin, sucralose, and neotame are 180, 200, 300, 600, and 7,000–13,000 times sweeter than sugar, respectively. Has their adoption led to taste distortion, and increased appetite for intensely sweet, highly caloric foods?
ASs might directly increase risk of weight gain in some individuals. Some studies have reported that AS use—or sweet taste itself—may increase hunger, cravings, or food intake (10,40–42), though most studies have reported no such increases (43,44). A few studies have reported elevated insulin and/or falling glucose levels (45–47).
Of particular concern are results from rodent studies. Elevated levels of aspartate—which constitutes 40% of aspartame—are toxic to neurons in the arcuate nucleus of the hypothalamus( 48,49), a key forebrain site for leptin signaling to reduce food intake (50,51). The earlier the exposure, the more profound the damage (52). Could aspartame exposure at high-normal levels cause neurotoxicity, with increased leptin resistance and obesity, in humans?

37. Children who sleep more eat fewer calories Monday 4 November 2013 - 3am PST
A new study finds that children who sleep more may eat fewer calories and put on less weight, strengthening the idea that obesity risk and lack of sleep are linked. Led by the Center for Obesity Research and Education (CORE) at Temple University in Philadelphia, PA, the study is thought to be the first to look at the effect of sleep on children's eating behaviors by manipulating their sleep time. A report on the study is scheduled to appear in a forthcoming issue of Pediatrics. First author Chantelle Hart, associate professor of public health at Temple's CORE, says: "Findings from this study suggest that enhancing school-age children's sleep at night could have important implications for prevention and treatment of obesity." The researchers enrolled 37 children aged from 8 to 11, among whom 27% were overweight or obese, to take part in the 3-week study. Changing sleep patterns For the first week the children slept as normal, but for the second and third week they were randomized to either sleep longer per night for one week and then less for another week, or sleep less for one week and then longer for another week. The children were weighed and asked about what they ate during the study period. They also had tests to measure fasting levels of leptin, a hormone that regulates hunger and is closely linked to body fat.

38. Children who sleep more eat fewer calories Monday 4 November 2013 - 3am PST
The results show that compared with the week of reduced sleep, for the week when the children slept more, they reported consuming an average of 134 fewer calories per day. They also weighed half a pound less and had lower levels of leptin. Prof. Hart says while these are still early results, the intervention looks promising and: "The potential role of sleep should be further explored." The team is now planning to undertake a study sponsored by the NIH's National Heart Lung and Blood Institute to see if getting kids to sleep more leads to significant changes in eating, activity and weight. Other studies have also suggested links between children's sleep patterns and weight gain. For example, in 2011, researchers in New Zealand reported in the BMJ that they found lack of sleep in young children was linked to obesity. Earlier this year, US researchers writing in the Proceedings of the National Academy of Sciences also suggested lack of sleep in adults is linked to weight gain. Prof. Hart concludes: "Given all of its documented benefits, in many ways, you can't lose in promoting a good night's sleep." Written by Catharine Paddock PhD

39. True or False
Hill’s guidelines of temporality is more easily established in a prospective than a retrospective study.
Strong associations are more likely to be causal.
All of Hill’s criteria are required to meet causality.
Exposure to HIV is a necessary cause of AIDS.
Exposure to HIV is a sufficient cause of AIDS.
Exposure to cigarette smoke is a necessary cause of lung cancer?
Exposure to cigarette smoke is a sufficient cause of lung cancer?
The presence of an association is indicative of a causal relationship.
Time order is an essential attribute of a cause.
If we have ruled out chance, bias, and confounding, as explanations for an association, we may conclude that the association is causal.
According to the sufficient-component causal model, blocking the action of a necessary cause will prevent all cases of a disease by all of its causal mechanisms.