MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability
- 1Center for Cancer Risk Analysis, MGH Cancer Center, Massachusetts General Hospital, Boston, MA, USA
- 2Centre for Epidemiology and Biostatistics, School of Public Health, Chinese University of Hong Kong, Hong Kong
- 3Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
- 4Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
- 5Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Correspondence to: Dr H Tsao Department of Dermatology/Massachusetts General Hospital, Bartlett 622, 48 Blossom Street, Boston, MA 02114;
- Received 1 March 2005
- Accepted 31 August 2005
- Revised 20 August 2005
- Published Online First 16 September 2005
Background: Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier.
Methods: We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation.
Results: From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic regression model (MELPREDICT) is given by where L = 1.99+[0.92×(no. of proband primaries)]+[0.74×(no. of additional family primaries)]−[2.11×ln(age)]. The mean estimated probabilities for subjects in the Boston dataset were 55.4% and 5.1% for the mutation carriers and non-carriers respectively. In a receiver operator characteristic analysis, the area under the curve was 0.881 (95% confidence interval 0.739 to 1.000) for the Boston model set (n = 116) and 0.803 (0.729 to 0.877) for an external Toronto hereditary melanoma cohort (n = 143).
Conclusions: These results represent the first-iteration logistic regression model to approximate CDKN2A carrier probability. Validation of this model with an external dataset revealed relatively robust performance.
- AUC, area under the curve
- PBL, peripheral blood leukocyte
- ROC, receiver operating characteristic
- SSCP, single strand conformation polymorphism
Published Online First 16 September 2005
Competing interests: there are no competing interests