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Dr. Zahid Ahmad Butt

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Cause An antecedent event, condition, or characteristic that was necessary for the occurrence of the disease at the moment it occurred, given that other conditions are fixed A cause of a disease occurrence is an event, condition, or characteristic that preceded the disease onset and that, had the event, condition, or characteristic been different in a specified way, the disease either would not have occurred at all or would not have occurred until some later time 2

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Cause can also be defined as something that brings about an effect or a result. Cause may lead to an effect (disease) but, it is not simple since several diseases are multifactorial. Cause

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Smoking causes lung cancer, chronic obstructive pulmonary disease, peptic ulcers, bladder cancer, coronary artery disease. Concepts of Cause

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Coronary Artery disease has multiple causes: cigarette smoking, high levels of LDL, stress, hormonal effects, hypertension, hypercholesterolemia, life style, lack of physical activity, heredity etc. Concepts of Cause contd..

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Because of diseases being multifactorial, the influence of peoples behaviours or characteristics of their environments and life style are also important causes of diseases than the pathogenic mechanisms. Concepts of Cause contd..

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Cardiovascular and cancer deaths can largely be traced to behavioural and environmental factors. The spread of AIDS is due primarily to sexual behaviours and drug use. Example

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Interpretations of causation 1. Mechanistic interpretation of causation (Lab researcher)To be termed a cause an agent must be both necessary and sufficient e.g. Kochs postulate One must be mindful that although Kochs postulate was developed for infectious diseases, they are not met for majority of these diseases e.g. polio virus, HIV/AIDS

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Interpretations of causation Mechanistic interpretations do not take into account inter-individual differences in susceptibility or interactions among causative agents.

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Interpretations of causation 2. Probabilistic interpretation Under this interpretation, a cause is something which leads to an increased probability that disease will occur. This interpretation also allows for the concept of interaction between causes. e.g. While it is believed that HIV causes AIDS, there is evidence that the probability of developing AIDS is lower in people who are infection by certain strains of the HIV virus.

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Interpretations of causation 3. Operational interpretation (public health based concept) A factor is a cause of if its elimination, or reduction in the level of exposure, leads to a decrease in occurrence of disease.

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Types of Causal Relationships A causal pathway can be either direct or indirect. In direct causation, a factor directly causes a disease without any intermediate step. In indirect causation, a factor causes a disease, but only through an intermediate step or steps. In human biology, intermediate steps are virtually always present in any causal process.

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Types of Causal Relationships contd.. If a relationship is causal, four types of causal relationships are possible: (1) necessary and sufficient; (2) necessary, but not sufficient; (3) sufficient, but not necessary; and (4) neither sufficient nor necessary.

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Figure 1. Direct versus indirect causes of disease. Downloaded from: StudentConsult (on 7 January 2014 09:14 AM) 2005 Elsevier

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Figure 2. Types of causal relationships: I. A factor is both necessary and sufficient. Downloaded from: StudentConsult (on 7 January 2014 09:14 AM) 2005 Elsevier

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Figure 3. Types of causal relationships: II. Each factor is necessary, but not sufficient. Downloaded from: StudentConsult (on 7 January 2014 09:14 AM) 2005 Elsevier

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Figure 4. Types of causal relationships: III. Each factor is sufficient, but not necessary. Downloaded from: StudentConsult (on 7 January 2014 09:14 AM) 2005 Elsevier

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Figure 5. Types of causal relationships: IV. Each factor is neither sufficient nor necessary. Downloaded from: StudentConsult (on 7 January 2014 09:14 AM) 2005 Elsevier

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Criteria for causality The following list is derived from an article by Sir Austin Bradford Hill (1965). The criteria were developed as a means to summarize scientific data on a postulated cause-effect relationship Today, with insights into disease manifestations as well as our limited knowledge of certain emerging diseases, not all criteria remain widely accepted, yet some do remain important.

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Criteria for causality Consistency of findings Strength of a relationship: Temporal sequence Dose response relationship Specificity: Biological plausibility Experimental evidence Reasoning by analogy Coherence of evidence

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1. Consistency of findings This refers to the repeated observations in other studies in different populations, different places, different times and under different circumstances. 2. Strength of a relationship: Magnitude of OR or RR Was OR or RR statistically significant However, weak relationships can still be of importance to public health if both exposure and disease are common.

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3. Temporal sequence: This refers to the temporal sequence of exposure and outcome is this sequence in the right direction Did the exposure cause the disease? Did the disease cause the exposure? Best evidence is from RCT and prospective study

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4. Dose response relationship (biological gradient): Those who are exposed more heavily, have a higher risk of disease than those exposed to lower doses. However associations that do not show an apparent trend of effect with an increase in dose, beware of unknown confounder Consider therefore: 1. Is a dose response relationship due to an unknown confounder 2. There may be threshold effects

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5. Specificity: One cause one outcome, i.e. the cause should lead to an effect not multiple effects Exposure: A disease should be specifically caused by a single exposure( not true in public health practice) Disease: An exposure should specifically cause one disease ( not true in public health practice) Specificity belongs more to mechanistic interpretation of cause rather than modern epidemiological interpretation.

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6. Biological plausibility: Does this association make sense? What are the known facts about the disease? 7. Experimental evidence: This refers to the quality of the chosen study type. You should ask yourself: Is the study type the strongest that could have been used under the circumstances (feasible and ethical)?

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8. Reasoning by analogy: This refers to the kind of reasoning which states- if one drug can cause birth defects then maybe another drug can also produce similar outcomes. 9. Coherence of evidence: This implies that a cause and effect interpretation of result does not conflict with what is generally known about the natural history and biology of disease.

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CriterionProblems with the criterion StrengthStrength depends on the prevalence of other causes and, thus, is not a biologic characteristic; could be confounded ConsistencyExceptions are understood best with hindsight SpecificityA cause can have many effects TemporalityIt may be difficult to establish the temporal sequence between cause and effect Biologic gradientCould be confounded; threshold phenomena would not show a progressive relation PlausibilityToo subjective CoherenceHow does it differ from consistency and plausibility? Experimental evidenceNot always available AnalogyAnalogies abound Table. Causal criteria of Hill 27

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Assessment of the Evidence suggesting Helicobacter Pylori as a causative agent of duodenal ulcers Temporal relationship. Helicobacter pylori is clearly linked to chronic gastritis. About 11% of chronic gastritis patients will go on to have duodenal ulcers over a 10-year period. In one study of 454 patients who underwent endoscopy 10 years earlier, 34 of 321 patients who had been positive for Helicobacter pylori (11%) had duodenal ulcer compared with 1 of 133 Helicobacter pylori-negative patients (0.8%).

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Assessment of evidence contd.. Strength of the relationship. Helicobacter pylori is found in at least 90% of patients with duodenal ulcer. In at least one population reported to lack duodenal ulcers, a northern Australian aboriginal tribe that is isolated from other people, it has never been found. Dose-response relationship. Density of Helicobacter pylori per square millimeter of gastric mucosa is higher in patients with duodenal ulcer than in patients without duodenal ulcer. Also see item 2 above.

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Assessment of evidence contd.. Replication of the findings. Many of the observations regarding Helicobacter pylori have been replicated repeatedly. Biologic plausibility. Although originally it was difficult to envision a bacterium that infects the stomach antrum causing ulcers in the duodenum, it is now recognized that Helicobacter pylori has binding sites on antral cells and can follow these cells into the duodenum. Helicobacter pylori also induces mediators of inflammation. Helicobacter pylori-infected mucosa is weakened and is susceptible to the damaging effects of acid.

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Assessment of evidence contd.. Consideration of alternate explanations. Data suggest that smoking can increase the risk of duodenal ulcer in Helicobacter pylori-infected patients but is not a risk factor in patients in whom Helicobacter pylori has been eradicated. Cessation of exposure. Eradication of Helicobacter pylori heals duodenal ulcers at the same rate as histamine receptor antagonists. Long-term ulcer recurrence rates were zero after Helicobacter pylori was eradicated using triple-antimicrobial therapy, compared with a 60% to 80% relapse rate often found in patients with duodenal ulcers treated with histamine receptor antagonists.

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Assessment of evidence contd.. Specificity of the association. Prevalence of Helicobacter pylori in patients with duodenal ulcers in 90% to 100%. However, it is found in some patients with gastric ulcer and even in asymptomatic individuals. Consistency with other knowledge. Prevalence of Helicobacter pylori infection is the same in men as in women. The incidence of duodenal ulcer, which in earlier years was believed to be higher in men than in women, has been equal in recent years.

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Assessment of evidence contd.. The prevalence of ulcer disease is believed to have peaked in the latter part of the 19th century, and the prevalence of Helicobacter pylori may have been much higher at that time because of poor living conditions. This reasoning is also based on observations today that the prevalence of Helicobacter pylori is much higher in developing countries.