Tandem mass spectrometry screening: proving effectiveness

Despite the considerable literature now emerging on screening by tandem mass spectrometry there are many points of uncertainty about test performance and much work to do in formalizing and validating follow-up protocols. The relative sensitivities of tandem mass spectrometry and previously-used diagnostic methods may differ for some diseases but not others, with the possibility of some metabolites being over-sensitive and diagnosing mild variants or non-disease. Cut-offs should be set using clinical rather than analytical criteria and at this early stage it is important that presumptive positive cases diagnosed through acylcarnitine profiling are compared as thoroughly as possible with symptomatic cases diagnosed using other techniques. Caution should be used in accepting mutation analysis as the ultimate diagnostic criterion. Consideration of incidence and careful examination of family history will all contribute to evidence of the equivalence or otherwise of screen-detected and symptomatic disease. Finally, there should be registration and long-term surveillance of all cases detected.