Predicting the likelihood of carrying a BRCA1 or BRCA2 mutation: validation of BOADICEA, BRCAPRO, IBIS, Myriad and the Manchester scoring system using data from UK genetics clinics.

OBJECTIVES: Genetic testing for the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has important implications for the clinical management of people found to carry a mutation. However, genetic testing is expensive and may be associated with adverse psychosocial effects. To provide a cost-efficient and clinically appropriate genetic counselling service, genetic testing should be targeted at those individuals most likely to carry pathogenic mutations. Several algorithms that predict the likelihood of carrying a BRCA1 or a BRCA2 mutation are currently used in clinical practice to identify such individuals. DESIGN: We evaluated the performance of the carrier prediction algorithms BOADICEA, BRCAPRO, IBIS, the Manchester scoring system and Myriad tables, using 1934 families seen in cancer genetics clinics in the UK in whom an index patient had been screened for BRCA1 and/or BRCA2 mutations. The models were evaluated for calibration, discrimination and accuracy of the predictions. RESULTS: Of the five algorithms, only BOADICEA predicted the overall observed number of mutations detected accurately (ie, was well calibrated). BOADICEA also provided the best discrimination, being significantly better (p<0.05) than all models except BRCAPRO (area under the receiver operating characteristic curve statistics: BOADICEA = 0.77, BRCAPRO = 0.76, IBIS = 0.74, Manchester = 0.75, Myriad = 0.72). All models underpredicted the number of BRCA1 and BRCA2 mutations in the low estimated risk category. CONCLUSIONS: Carrier prediction algorithms provide a rational basis for counselling individuals likely to carry BRCA1 or BRCA2 mutations. Their widespread use would improve equity of access and the cost-effectiveness of genetic testing.

Issues concerning the evaluation and regulation of predictive genetic testing.

This paper is a précis of my keynote address at the Symposium on Predictive Genetic Testing organised by the Robert Koch Institute in Berlin. The talk is based on reflections which I have had over a number of years on genetic testing and its evaluation and regulation. It presents a thesis, which I hope will generate discussion and comment. A theme which will run through the paper is the need for precise definition of terms before making any normative statement about such terms. Our failure to do so in genetic discourse is at best confusing and at worst capable of resulting in inappropriate (and sometimes harmful) regulatory responses.

The impact of genomics on public health practice: the case for change.

Public health practice will not be able in the 21st century to ignore the impact of genomics, cell and molecular biology. It will need to take into consideration issues that include, among others: the complementary nature of social and biological models of disease, genetic exceptionalism, the readiness of public and patient to respond to genomic information, the relationship between individuals and populations, and concepts of population stratification. Health systems will need to adapt their practice and organisation to include new sequencing technologies, bioinformatic expertise and proper evaluation of genetic and molecular tests. Links with the commercial sector will increase in importance. The impact on developing countries cannot be ignored and will require special attention.

Genetic testing: a conceptual exploration.

This paper attempts to explore a number of conceptual issues surrounding genetic testing. It looks at the meaning of the terms, genetic information and genetic testing in relation to the definition set out by the Advisory Committee on Genetic Testing in the UK, and by the Task Force on Genetic Testing in the USA. It argues that the special arrangements that may be required for the regulation of genetic tests should not be determined by reference to the nature or technology of the test, but by considering those morally relevant features that justify regulation. Failure to do so will lead to the regulation of genetic tests that need not be regulated, and would fail to cover other tests which should be regulated. The paper also argues that there is little in the nature of the properties of gene tests, using DNA or chromosomes, that in itself justifies a special approach.

Transient visually evoked potentials to the pattern reversal and onset of sinusoidal gratings.

Transient visually evoked potentials (VEPs) recorded in response to the contrast reversal and onset of spatially sinusoidal gratings have been investigated. Previous reports of an increase in the latency of the response at higher spatial frequencies have been confirmed but only for spatial frequencies higher than 2 c/deg. At lower spatial frequencies it is suggested that two positive components interact resulting in a departure from a monotonic relationship between latency and spatial frequency. Below 1 c/deg pattern reversal and pattern onset modes of stimulation produced VEPs of similar amplitude and wave form. Above 1 c/deg the amplitude of the pattern onset response peaked at a higher spatial frequency than the response to pattern reversal, and the response was dominated by a negative (N1) rather than a positive component (P1). This distinction has been corroborated by investigating the effect of field size variation. The peak amplitudes shifted to a lower spatial frequency with increase in field size but at all field sizes the N1 component of the pattern onset response peaked at a higher spatial frequency than the other components measured. It is attempted to relate these findings to previous studies of both grating and checkerboard VEPs and to psychophysical studies of contrast sensitivity.

Subtle disturbances of vision after optic neuritis elicited by studying contrast sensitivity.

Eight patients with a subjective disorder of vision yet normal Snellen acuities after optic neuritis were shown to have an abnormal contrast sensitivity function in their affected eye. It appears that certain disorders of vision are associated with an abnormality of the contrast sensitivity function in spite of near normal visual acuity. Such an abnormality may affect pattern recognition without having an influence on Snellen acuity because of the high contrast of the latter and its predominant association with the higher spatial frequencies. Contrast sensitivity function is thus the only tool available to study those aspects of vision which have remained impervious to other subjective tests of visual function.