The addition of appropriate comparison groups in a survey of patients treated with a specific intervention for fatigue can provide more information, even if the design is non-randomized and open-label. Comparison groups can be retrospective or prospective. Prospectively assessed patients who are similar to those who receive the study intervention and undergo identical assessment yield much more credible data.

To enhance the credibility of the data obtained from these designs, the comparison group must be similar to the study group, or distinct from the study group in some systematic way that can be statistically controlled after the data are collected. In some cases, it is worthwhile to match the study and comparison groups on one or more key variables, such as age and gender, or specific fatigue-related or disease-related variables.

Resources permitting, it may be valuable to identify several comparison groups, each of which may assess different aspects of the treatment. For example, a study of an exercise protocol in patients with metastatic cancer may yield interesting "pre-post" information about energy level and mental clarity, and similarly important information about potential adverse effects. Collection of data from similar but untreated patients would be the comparison of first priority. If feasible, however, additional comparisons, such as the effect of the exercise protocol on fatigued patients following curative resection of the same disease would be informative.