Validation of a clinical breast cancer risk assessment tool combining a polygenic score for all ancestries with traditional risk factors.

PURPOSE: We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort. METHODS: This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs. RESULTS: Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC. CONCLUSION: CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.

Correction: Inaccuracies and shortcomings in "Adherence of cell-free DNA noninvasive prenatal screens to ACMG recommendations".

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Psychiatrists' views of the genetic bases of mental disorders and behavioral traits and their use of genetic tests.

We examined how 372 psychiatrists view genetic aspects of mental disorders and behaviors and use genetic tests (GTs). Most thought that the genetic contribution was moderate/high for bipolar disorder, schizophrenia, depression, Alzheimer's, intelligence, creativity, anxiety, and suicidality. In the past 6 months, 14.1% ordered GTs, 18.3% discussed prenatal testing with patients, 36.0% initiated discussions about other GTs, 41.6% had patients ask about GTs, and 5.3% excluded GT results from patient records. Many thought that GTs; were available for schizophrenia (24.3%) and major depression (19.6%). Women were more likely to report that patients asked about GTs; and were less certain about the degree of genetic contribution to several disorders. Psychiatrists perceive strong genetic bases for numerous disorders and traits, and many have discussed and ordered tests for GTs, but have relatively limited knowledge about available tests. These data suggest possible sex differences in psychiatrists' beliefs about genetic contributions to disorders and have implications for future research, education, policy, and care.

Use of genetic tests among neurologists and psychiatrists: knowledge, attitudes, behaviors, and needs for training.

This study explores neurologists' and psychiatrists' knowledge, attitudes, and practices concerning genetic tests. Psychiatrists (n = 5,316) and neurologists (n = 2,167) on the American Medical Association master list who had agreed to receive surveys were sent an email link to a survey about their attitudes and practices regarding genetic testing; 372 psychiatrists and 163 neurologists responded. A higher proportion of neurologists (74%) than psychiatrists (14%) who responded to the survey had ordered genetic testing in the past 6 months. Overall, most respondents thought that genetic tests should be performed more frequently, but almost half believed genetic tests could harm patients psychologically and considered legal protections inadequate. Almost half of neurologists (49%) and over 75% of psychiatrists did not have a genetics professional to whom to refer patients; those who had ordered genetic tests were more likely than those who did not do so to have access to a genetic counselor. Of respondents, 10% had received patient requests not to document genetic information and 15% had received inquiries about direct-to-consumer genetic testing. Neurologists reported themselves to be relatively more experienced and knowledgeable about genetics than psychiatrists. These data, the first to examine several important issues concerning knowledge, attitudes and behaviors of neurologists and psychiatrists regarding genetic tests, have important implications for future practice, research, and education.