Table 4.

Evaluation of the potential causal relationship between SBP variability and diabetic foot ulceration using epidemiologic criteria

	Expected relationship	Evidence
Temporal relationship	Exposure to the potential causative agent should occur before disease develops	Cases were limited to patients with incident diabetic foot ulcers and BP measures taken during 1-year period before foot ulceration were used to compute SBP variability. Therefore, SBP variability preceded foot ulceration in our study
Strength of the association	Stronger associations are more likely to be causal	In our model, the adjusted odds ratios for SBP variability were similar in magnitude to established risk factors for foot ulceration, such as neuropathy
Dose-response relationship	As the dose of exposure increases, so should the risk	As SBP variability increased across the quartiles, so did the risk of foot ulceration
Replication of the findings	A causal relationship should be found across different studies and populations	This is the first study identifying an association between SBP variability and foot ulceration
Biologic plausibility	A reasonable biologic mechanism should underpin the epidemiologic association	Pathophysiologic pathways need to be explored further, although there is evidence to support biologic plausibility [29,31,33,35]
Consideration of alternative explanations	Is the association causal or confounding?	Our models attempt to control for factors known to increase the risk of developing a foot ulcer, however, residual confounding will always be a concern in case-control and cohort studies. Prospective, randomized trials would better address this
Cessation of exposure	The risk of a disease should decline when exposure to the potential causative agent is reduced or eliminated	Calcium channel blockers reduce exposure to SBP variability and were protective in our analysis
Consistency with other knowledge	The potential causative association should fit with what is known more generally about both the causative agent and disease state	In addition to diabetic foot ulcers, increasing SBP variability has been associated with other microvascular and macrovascular complications [1–6]

Data from [34].