Showing papers by "Wenyi Wang published in 2006"

Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome

Abstract: ContextIdentifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.ObjectiveTo develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.Design, Setting, and PatientsExternal validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Main Outcome MeasureAbility of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.ResultsIn the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.ConclusionsMMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness.

Abstract: Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed This probability will be useful as additional information to decide whether or not a genetic test should be performed This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed This model works well, especially in homozygous carriers, showing a high discriminative power This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders