Testing for differences in polygenic scores in the presence of confounding.

Polygenic scores have become an important tool in human genetics, enabling the prediction of individuals' phenotypes from their genotypes. Understanding how the pattern of differences in polygenic score predictions across individuals intersects with variation in ancestry can provide insights into the evolutionary forces acting on the trait in question, and is important for understanding health disparities. However, because most polygenic scores are computed using effect estimates from population samples, they are susceptible to confounding by both genetic and environmental effects that are correlated with ancestry. The extent to which this confounding drives patterns in the distribution of polygenic scores depends on patterns of population structure in both the original estimation panel and in the prediction/test panel. Here, we use theory from population and statistical genetics, together with simulations, to study the procedure of testing for an association between polygenic scores and axes of ancestry variation in the presence of confounding. We use a general model of genetic relatedness to describe how confounding in the estimation panel biases the distribution of polygenic scores in a way that depends on the degree of overlap in population structure between panels. We then show how this confounding can bias tests for associations between polygenic scores and important axes of ancestry variation in the test panel. Finally, we use the understanding gained from this analysis to develop a method that uses patterns of genetic similarity between the two panels to guard against these biases, and show that this method can provide better protection against confounding than the standard PCA-based approach.

Prospective Multicenter Diagnostic Performance of Technologist-Performed Screening Breast Ultrasound After Tomosynthesis in Women With Dense Breasts (the DBTUST).

PURPOSE: To assess diagnostic performance of digital breast tomosynthesis (DBT) alone or combined with technologist-performed handheld screening ultrasound (US) in women with dense breasts. METHODS: In an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant multicenter protocol in western Pennsylvania, 6,179 women consented to three rounds of annual screening, interpreted by two radiologist observers, and had appropriate follow-up. Primary analysis was based on first observer results. RESULTS: Mean participant age was 54.8 years (range, 40-75 years). Across 17,552 screens, there were 126 cancer events in 125 women (7.2/1,000; 95% CI, 5.9 to 8.4). In year 1, DBT-alone cancer yield was 5.0/1,000, and of DBT+US, 6.3/1,000, difference 1.3/1,000 (95% CI, 0.3 to 2.1; P = .005). In years 2 + 3, DBT cancer yield was 4.9/1,000, and of DBT+US, 5.9/1,000, difference 1.0/1,000 (95% CI, 0.4 to 1.5; P < .001). False-positive rate increased from 7.0% for DBT in year 1 to 11.5% for DBT+US and from 5.9% for DBT in year 2 + 3 to 9.7% for DBT+US (P < .001 for both). Nine cancers were seen only by double reading DBT and one by double reading US. Ten interval cancers (0.6/1,000 [95% CI, 0.2 to 0.9]) were identified. Despite reduction in specificity, addition of US improved receiver operating characteristic curves, with area under receiver operating characteristic curve increasing from 0.83 for DBT alone to 0.92 for DBT+US in year 1 (P = .01), with smaller improvements in subsequent years. Of 6,179 women, across all 3 years, 172/6,179 (2.8%) unique women had a false-positive biopsy because of DBT as did another 230/6,179 (3.7%) women because of US (P < .001). CONCLUSION: Overall added cancer detection rate of US screening after DBT was modest at 19/17,552 (1.1/1,000; CI, 0.5- to 1.6) screens but potentially overcomes substantial increases in false-positive recalls and benign biopsies.

Exploring the use of cobalt(II) dipolar shifts in refining the structure of a zinc finger peptide.

The uses of dipolar shifts due to cobalt(II) substituted for zinc(II) in a consensus zinc finger peptide for refining the NMR-determined structure were examined. Substantial differences between the calculated and observed chemical shift differences between the cobalt(II) and zinc(II) complexes were observed when these dipolar shifts were not used as constraints in the structure refinement. However, inclusion of these constraints resulted in excellent agreement with minor adjustments in the structure and a slight improvement in the precision of the structure determination. Other calculations revealed that the dipolar shifts were not adequate to determine the overall folded structure by themselves, but were useful in increasing the accuracy and precision of a structure determined based only on nuclear Overhauser effects constraints involving only backbone atoms.

Polygenic score accuracy in ancient samples: Quantifying the effects of allelic turnover.

Polygenic scores link the genotypes of ancient individuals to their phenotypes, which are often unobservable, offering a tantalizing opportunity to reconstruct complex trait evolution. In practice, however, interpretation of ancient polygenic scores is subject to numerous assumptions. For one, the genome-wide association (GWA) studies from which polygenic scores are derived, can only estimate effect sizes for loci segregating in contemporary populations. Therefore, a GWA study may not correctly identify all loci relevant to trait variation in the ancient population. In addition, the frequencies of trait-associated loci may have changed in the intervening years. Here, we devise a theoretical framework to quantify the effect of this allelic turnover on the statistical properties of polygenic scores as functions of population genetic dynamics, trait architecture, power to detect significant loci, and the age of the ancient sample. We model the allele frequencies of loci underlying trait variation using the Wright-Fisher diffusion, and employ the spectral representation of its transition density to find analytical expressions for several error metrics, including the expected sample correlation between the polygenic scores of ancient individuals and their true phenotypes, referred to as polygenic score accuracy. Our theory also applies to a two-population scenario and demonstrates that allelic turnover alone may explain a substantial percentage of the reduced accuracy observed in cross-population predictions, akin to those performed in human genetics. Finally, we use simulations to explore the effects of recent directional selection, a bias-inducing process, on the statistics of interest. We find that even in the presence of bias, weak selection induces minimal deviations from our neutral expectations for the decay of polygenic score accuracy. By quantifying the limitations of polygenic scores in an explicit evolutionary context, our work lays the foundation for the development of more sophisticated statistical procedures to analyze both temporally and geographically resolved polygenic scores.

Cancer Yield Exceeds 2% for BI-RADS 3 Probably Benign Findings in Women Older Than 60 Years in the National Mammography Database.

Background Breast Imaging Reporting and Data System (BI-RADS) category 3 (BR3) (probably benign) mammographic assessments are reserved for imaging findings known to have likelihood of malignancy of 2% or less. Purpose To determine the effect of age, finding type, and prior mammography on cancer yield for BR3 findings in the National Mammography Database (NMD). Materials and Methods This HIPAA-compliant retrospective cohort institutional review board-exempt study evaluated women recalled from screening mammography followed by BR3 assessment at diagnostic evaluation from January 2009 to March 2018 and from 471 NMD facilities. Only the first BR3 occurrence was included for women with biopsy or imaging follow-up of at least 2 years. Women with a history of breast cancer or who underwent biopsy at time of initial BR3 assessment were excluded. Women were stratified by age in 10-year intervals. Cancer yield was calculated for each age group, with (for presumed new findings) and without prior mammographic comparison, and by lesion type, where available. Linear regression with weighted-age binning was performed to assess for differences between groups; P < .05 was indicative of a significant difference. Results A total of 1 380 652 (18.2%) women were recalled after screening mammography, of whom 157 130 (11.4%) were given a BR3 assessment within 90 days after screening. Of these, 43 628 women (median age, 55 years; age range, 25-90 years) had adequate follow-up for analysis. Cancer yield increased with increasing age decile, ranging from 0.51% (six of 1167) in women aged 30-39 years to 4.63% (41 of 885) in women aged 80-90 years; cancer yield exceeded 2% at and after age 59.7 years for baseline findings and at and after age 53.6 years for presumed new findings, although there was no effect on stage distribution. Cancer yield for baseline BR3 masses was 10 of 2111 (0.47% [95% CI: 0.24, 0.90]) versus 47 of 3003 (1.57% [95% CI: 1.16, 2.09]) with prior comparisons (P < .001); cancer yield for baseline calcifications was eight of 929 (0.86% [95% CI: 0.40, 1.76]) versus 84 of 2999 (2.80% [95% CI: 2.23, 3.47]) with prior comparisons (P < .001). Difference in cancer yield was 0.51% (95% CI: 0.16, 0.86) between women with and women without prior comparison at the same age (P = .006). Conclusion Cancer yield exceeded the 2% threshold for women aged 60 years or older and reached 4.6% for women aged 80-89 years. Breast Imaging Reporting and Data System 3 findings in women with a prior comparison had higher cancer yield than in those without a prior comparison at the same age. © RSNA, 2021 Online supplemental material is available for this article.

How well can we separate genetics from the environment?

A simulation study demonstrates a better method for separating genetic effects from environmental effects in genome-wide association studies, but there is still some way to go before this becomes a "solved" problem.

Cancer Yield and Patterns of Follow-up for BI-RADS Category 3 after Screening Mammography Recall in the National Mammography Database.

Background The literature supports the use of short-interval follow-up as an alternative to biopsy for lesions assessed as probably benign, Breast Imaging Reporting and Data System (BI-RADS) category 3, with an expected malignancy rate of less than 2%. Purpose To assess outcomes from 6-, 12-, and 24-month follow-up of probably benign findings first identified at recall from screening mammography in the National Mammography Database (NMD). Materials and Methods This retrospective study included women recalled from screening mammography with BI-RADS category 3 assessment at additional evaluation from January 2009 through March 2018 from 471 NMD facilities. Only the first BI-RADS category 3 occurrence for women aged 25 years or older with no personal history of breast cancer was analyzed, with biopsy or 2-year imaging follow-up. Cancer yield and positive predictive value of biopsies performed (PPV3) were determined at each follow-up. Results Among 45 202 women (median age, 55 years; range, 25-90 years) with a BI-RADS category 3 lesion, 1574 (3.5%) underwent biopsy at the time of lesion detection, yielding 72 cancers (cancer yield, 4.6%; 72 of 1574 women). For the remaining 43 628 women who accepted surveillance, 922 were seen within 90 days (with 78 lesions biopsied and 12 [15%] classified as malignant). The women still in surveillance (31 465 of 43 381 women [72.5%]) underwent follow-up mammography at 6 months. Of 3001 (9.5%) lesions biopsied, 456 (15.2%) were malignant (cancer yield, 1.5%; 456 of 31 465 women; 95% confidence interval [CI]: 1.3%, 1.6%). Among 18 748 of 25 997 women (72.1%) in surveillance who underwent follow-up at 12 months, 1219 (6.5%) underwent biopsy with 230 (18.9%) malignant lesions found (cancer yield, 1.2%; 230 of 18 748 women; 95% CI: 1.1%, 1.4%). Through 2-year follow-up, the biopsy rate was 11.2% (4894 of 43 628 women) with a cancer yield of 1.86% (810 malignancies found among 43 628 women; 95% CI: 1.73%, 1.98%) and a PPV3 of 16.6% (810 malignancies found among 4894 women). Conclusion In the National Mammography Database, Breast Imaging Reporting and Data System (BI-RADS) category 3 use is appropriate, with 1.86% cumulative cancer yield through 2-year follow-up. Of 810 malignancies, 468 (57.8%) were diagnosed at or before 6 months, validating necessity of short-interval follow-up of mammographic BI-RADS category 3 findings. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Moy in this issue.

Measuring intolerance to mutation in human genetics.

In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples-genes that appear 'intolerant' to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency.