From experimental units to unique experiments: chronobiologic pilots complement large trials.

The timing of treatment affects outcome. For mapping multi-frequency rhythm spectra first to optimize chronochemotherapy, 1000 marker determinations on the subject are more informative than a few determinations on each of hundreds of patients. N-of-6 subgroups should follow, with one subject assigned to each of 6 marker rhythm stages, 60 (e.g. 4 hours on a 24-hour scale) apart. Once the time structure has been mapped, minimal sampling requirements determined, and guidelines for treatment established, the information gained from chronobiologic n-of-1 and n-of-6 test pilot designs can be built cost-effectively into randomized controlled trials to benefit large patient populations. Sequential tests combined with marker rhythmometry and cosinor analysis on single test subjects, small groups and eventually on each patient are powerful tools that can extract information otherwise unattainable even at great cost and bring the P-value from publications to the patients.