Diagnostic accuracy and linkage analysis: how useful are schizophrenia spectrum phenotypes?

OBJECTIVE: Numerous studies suggest that the nonschizophrenic relatives of schizophrenic patients exhibit psychiatric and other features that discriminate them from normal comparison subjects. These features have been put forth as "spectrum" phenotypes that may be variant manifestations of the schizophrenia genotype. However, most of these studies do not address a key measurement question: does the diagnostic accuracy of these spectrum classifications warrant their use in genetic linkage studies of schizophrenia? METHOD: The authors reviewed 30 studies of putative indicators of the schizophrenic genotype: schizotypal personality disorder, eye tracking dysfunction, attentional impairment, auditory evoked potentials, neurological signs, neuropsychological impairment, and allusive thinking. RESULTS: Although each of 42 measures of these indicators discriminated the relatives of schizophrenic patients from the normal comparison subjects, a diagnostic accuracy analysis suggested that only six of these would improve the informativeness of genetic linkage data. CONCLUSIONS: Many proposed spectrum phenotypes for schizophrenia may not be useful for linkage analysis because of high false positive rates (poor specificity). Future work aimed at describing and developing phenotypes for linkage analysis should assess the diagnostic accuracy of proposed measures.