Table 1.

Advantages and limitations of different lines of evidence

Lines of Evidence	Advantages	Limitations
Epidemiological/Cohort Studies	•Large number of subjects	•Association not causation; difficult to determine the ‘direction’ of cause/effect for exposure/outcome (reverse causality problem)
	•Data on multiple factors
	•Longitudinal follow-up over many years
		•Uncertainty about the influence of unidentified factors
		•Uncertainty about whether an intervention aimed at an identified factor would have an impact on biological or clinical outcome
Basic Science/Animal Studies	•Investigation under highly controlled conditions	•Reduction of complex issues into simple ones
	•Determination of underlying mechanisms •Identification of intervening variables that help explain clinical outcomes (e.g., changes in brain structure, neurotransmitters, growth factors, inflammatory markers, etc.)	•Need to translate findings from basic science or animal models to the study of humans
		•Elucidating underlying mechanisms does not signify that manipulating an identified factor will alter clinical outcome
Human “Proof-of-Concept” Studies	•Opportunity to examine markers of cerebral plasticity, reserve, efficiency, and neural compensation	•Similar to limitations of basic science/animal studies noted above
	•Utilization of tools of cognitive neuroscience to elucidate underlying mechanism
	•Opportunity for further hypothesis testing and generation
Human Intervention Studies	•Often considered the “gold standard” •Randomization helps control for selection bias and other variables that may influence clinical outcomes •Outcome measures can include cognitive performance as well as biological or neuroimaging markers	•Potential feasibility concerns, including financial, logistical, or ethical barriers
		•Uncertainty about the generalizability of observed effects to other populations or settings
		•Uncertainty about whether statistically significant results are clinically relevant
		•Uncertainty about whether a study outcome is due to a particular dose/duration of an intervention, or characteristics of the particular sample

Table modified from Daffner 2010 [1].