1	Exposure problems, including misclassification	e.g., mistiming of exposure relative to outcome assessment, lack of adequate variability in exposure, poor exposure assessment method
2	Outcome problems, including misclassification	e.g., reliance on clinical databases, instrument grossly mismatched to participants’ abilities
3	Confounding, defined as bias due to unmeasured or poorly accounted for common causes (or correlates of such common causes) of the exposure and outcome of interest.	e.g., inadequate adjustment, overadjustment
4	Selection Bias – Cohort Formation, defined as bias which occurs when potentially eligible participants are not included in the study during enrollment in such a way that it leads to an association between the exposure and outcome that induces an association that would not have been present had those persons not been excluded	e.g., exclusion of persons with common chronic disease
5	Selection Bias – Loss to Follow-up, bias which occurs when potentially eligible participants are lost to follow-up in such a way that it leads to an association between the exposure and outcome that would not have been present had those persons not been lost	e.g. severe loss of participants (>25%) over the follow-up period in combination with lack of pertinent information on relation between exposure or outcome and loss
6	Generalizability, the expectation that the reported results would be consistent had the trial been completed in a second population of interest	e.g. highly selected population
7	Inappropriate Adjustments	e.g. main analyses adjusted for one or more possible intermediates
8	Interpretation Challenges	e.g. inappropriate statistical model, inappropriate study design