An Analysis of the Predictive Probability of the In Vitro Contracture Test for Determining Susceptibility to Malignant Hyperthermia

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Abstract
An objective estimate of the likelihood of correct designa- tion of malignant hyperthennia (MH) susceptibility from in vitro contractme test @/'CT) results is essential if genetic linkage studies of MH are to be more informative. The aim of this study was to generate and test statistical models that could be used to predict the probability of susceptibil- ity of an individual to MH from the results of their lVCTs. Logistic regression of the IVCT results of an index group of 50 patients (age range 9-73 years; MH susceptible (MHS), n = 13; MH normal (MHN), n = 32; MH equivocal IMHEJ, n = 5) who were either at low risk of MH or were proband cases were used to generate models to predict probability of MH susceptibility. Models incorporated data from individual contra&me tests or from combiua- tions of tests (static halothane, dynamic halotbane, caf- feine, ryanodine) performed according to the protocols of the European Malignant Hypertbermia Group. Of the in- dividual contracture tests, the ryanodine test was most closely correlated with MH status. Discriminatory ability of the models was assessed using receiver operating char- acteristic (ROC) curves. Inclusion of predictor variables from the ryanodine, caffeine, and dynamic halo&me tests improved upon the discriminatory ability of the models incorporating variables from individual tests and was considered to be the best model. The reproducibility of this model was confirmed using an ROC curve con- structed using data from 47 patients (age range lo- 62 years; MHS, n = 15; MHN, n = 28; MHE, n = 4) who were classified in a way similar to the index group. A fur- ther group of 153 patients (age range 9-74 years; MHS, n = 44; MHN, YI = 92; MHE, n = 17) who were consecu- tively tested relatives of susceptible individuals was used to assess the generalizability of the best model. The model met the criteria for a useful discriminatory model with this group of patients, 125 of whom (including 9 MHE pa- tients) could be designated as positive or negative for MH with a likelihood of more than 95%. The logistic regression models provide objective likelihoods for the MH pheno- type that could be usefully incorporated into genetic link- age studies of the condition.