Table 4 Bradford Hill criteria for assessing causation in cohort studies and interpretations to be used in this review

1. Strength of the association

The stronger the association between a risk factor and outcome, the more likely the relationship is to be causal

*For strength of association we will use odds ratio which will be graded as 1, 2, 3, 4 with 4 being strong association, 3 being moderate, 2 being weak association and 1 protective [46]

2. Consistency of findings

Have the same findings been observed among different populations, in different study designs and different times?

Findings of associations between psychological factors and symptom exacerbation have been established in other populations

3. Specificity of the association

When a single assumed cause produces a specific effect outcome

This is not going to be evaluated because single exposure to psychological factors and outcome of symptom relapse does not preclude a causal relationship

4. Temporal sequence of association

Exposure must precede outcome

Analyses will be restricted to prospective cohort studies, a design that ensures exposure will precede outcome

5. Biological gradient

Changes in disease rates should be associated with changes in exposure (dose–response)

Changes in disease (symptom) activity should correspond to changes in exposure (length or intensity of exposure to psychological factors or degree of stress experienced)

6. Biological plausibility

Presence of a potential biological mechanism of causality

Exposure selected in this review meets the criteria for plausibility of scientific credible mechanism for causality [15, 17]

7. Coherence

Does the relationship agree with the current knowledge of the natural history/biology of the disease?

Current evidence needs to support an association between psychological factors and symptom relapse

8. Experiment

Does the removal of the exposure alter the frequency of the outcome?

There are experimental studies supporting the plausibility of causal relationship between psychological factors and symptom exacerbation [47]