The relevance of design issues and new methods It is sad to comment on work of a founding father of clinical epidemiology, who so profoundly enjoyed the scientific debate, without him being able to respond. But it is not only sad, it is also a great honour to have the opportunity to discuss one of the last pieces of this great architect of clinical research.1 The points made by Alvan Feinstein are clear and I agree with most of his analysis, but some additional challenges should be emphasised. Indeed, apart from interpretative problems, “nosological indices” such as sensitivity and specificity are problematic as they will vary with the spectrum and selection of patients.2–4 However, also “diagnostic indices” (predictive accuracy) are not constants. Taking account of all relevant covariables is, if at all useful, generally impossible because many of these are not clear, unmeasurable, or too particularistic for a useful general evaluation. So, we must not overemphasise the value of diagnostic indices. And where we use them, we must be very specific as to objective, context, and setting. We should also be keen on setting specific external validation when we want to generalise observed index values for clinical purposes. Acknowledging all this, it cannot be denied that for clinical and epidemiological purposes there is often a need to use “nosological indices” to communicate general characteristics of a test. Also Feinstein did …