Timing | Identification of phenotypes precedes systematic collection of data | Systematic collection of data precedes identification of phenotypes |
Derivation | ‘Top-down’: theory informs data collection and interpretation | ‘Bottom-up’: unbiased data collection informs subsequent theory |
Size of derivation cohort | Derived from limited, single-centre experiences | Derived from large, multicentre cohorts |
Validation | Contingent on the specific population and biases of the observer | Robust across multiple cohorts, independent of observer |
Internal coherence | Features are inconsistently associated with each other across patients (e.g. physiology and imaging) | Phenotype-defining features, by design, are internally consistent in their relationship to each other |
Relationship to underlying biology | Reflects a simplistic or incorrect model of underlying pathophysiology | Reflects meaningful differences in underlying pathophysiology |
Complexity | Anchored on one or two clinically apparent variables | Incorporates high-dimensional data with non-linear interactions between variables |
Discreteness, continuity | Purported phenotypes are merely extremes of a normally distributed continuum | Phenotypes represent distinct “clusters,” meaningfully divergent from each other and their attributes cannot be explained by a single variable |
Impact on practice | Immediately used to justify changes in practice | Prospectively tested in phenotype-informed clinical trials |