The repetitive nature and complexity of some medically relevant genes poses a challenge for their accurate analysis in a clinical setting. The Genome in a Bottle Consortium has provided variant benchmark sets, but these exclude nearly four hundred medically relevant genes due to their repetitiveness or polymorphic complexity. Here we characterize 273 of these 395 challenging autosomal genes using a haplotype-resolved whole-genome assembly. This curated benchmark reports over 17,000 single nucleotide variations, 3,600 INDELs, and 200 structural variations each for human genome reference GRCh37 and GRCh38 across HG002. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically relevant genes including CBS , CRYAA , and KCNE1 . When masking these false duplications, variant recall can improve from 8% to 100%. Forming benchmarks from a haplotype-resolved whole-genome assembly may become a prototype for future benchmarks covering the whole genome.

BACKGROUNDTo evaluate associations between race and breast carcinoma treatment.METHODSData from 984 black and 849 white Medicare beneficiaries 67 years or older with local breast carcinoma and a subset of 732 surviving women interviewed 3–4 years posttreatment were used to calculate adjusted odds of treatment, controlling for age, comorbidity, attitudes, region, and area measures of socioeconomic and health care resources.RESULTSSixty‐seven percent of women received a mastectomy and 33% received breast‐conserving surgery. The odds of radiation omission were 48% higher (95% confidence interval [CI] 1.01–2.19) for blacks than for whites after considering covariates, but the absolute number of women who failed to receive this modality was small (11%). In race‐stratified models, the odds of having radiation omitted were significantly higher among blacks living greater distances from a cancer center (vs. lesser) or living in areas with high poverty (vs. low), but these factors did not affect radiation use among whites. Among those interviewed, blacks reported perceiving more ageism and racism in the health care system than whites (P = 0.001). The independent odds of receiving mastectomy (vs. breast conservation and radiation) were 2.72 times higher (95% CI 1.25–5.92) among women reporting the highest quartile of perceived ageism scores, compared with the lowest, and higher perceived ageism tended to be associated with higher odds of radiation omission (P = 0.06).CONCLUSIONSOlder black women with localized breast carcinoma may have a different experience obtaining treatment than their white counterparts. The absolute number of women receiving nonstandard care was small and the effects were small to moderate. However, if these patterns persist, it will be important to evaluate whether such experiences contribute to within‐stage race mortality disparities. Cancer 2002;95:1401–14. © 2002 American Cancer Society.DOI 10.1002/cncr.10825

Body image is important for many older women, and receiving treatment consistent with preferences about appearance was important in long-term mental health outcomes. Health professionals should elicit preferences about appearance from women and provide treatment choices in concordance with these preferences. Enhancing shared decision making has the potential to improve mental health in older breast cancer survivors.

The current system of providing a choice between mastectomy and breast conservation surgery is economically attractive when the economic analysis includes the benefit of patient choice of treatment.

Supplementary Material is available at Bioinformatics online.

BackgroundThe nuclear factor-KappaB (NF-κB) pathway is conserved from fruit flies to humans and is a key mediator of inflammatory signaling. Aberrant regulation of NF-κB is associated with several disorders including autoimmune disease, chronic inflammation, and cancer, making the NF-κB pathway an attractive therapeutic target. Many regulatory components of the NF-κB pathway have been identified, including microRNAs (miRNAs). miRNAs are small non-coding RNAs and are common components of signal transduction pathways. Here we present a cell-based functional genomics screen to systematically identify miRNAs that regulate NF-κB signaling.ResultsWe screened a library of miRNA mimics using a NF-κB reporter cell line in the presence and absence of tumor necrosis factor (+/- TNF). There were 9 and 15 hits in the -TNF and +TNF screens, respectively. We identified putative functional targets of these hits by integrating computational predictions with NF-κB modulators identified in a previous genome-wide cDNA screen. miR-517a and miR-517c were the top hits, activating the reporter 86- and 126-fold, respectively. Consistent with these results, miR-517a/c induced the expression of endogenous NF-κB targets and promoted the nuclear localization of p65 and the degradation of IκB. We identified TNFAIP3 interacting protein1 (TNIP1) as a target and characterized a functional SNP in the miR-517a/c binding site. Lastly, miR-517a/c induced apoptosis in vitro, which was phenocopied by knockdown of TNIP1.ConclusionsOur study suggests that miRNAs are common components of NF-κB signaling and miR-517a/c may play an important role in linking NF-κB signaling with cell survival through TNIP1.

Objective. To determine whether area-level Medicare physician fees for mastectomy and breast conserving surgery were associated with treatment received by Medicare beneficiaries with localized breast cancer and to compare these results with an earlier analysis conducted using small areas (three-digit zip codes) as the unit of observation. Data Source. Medicare claims and physician survey data for a national sample of elderly (aged 67 or older) Medicare beneficiaries with localized breast cancer treated in 1994 (unweighted n 5 1,787). Study Design. Multinomial logistic regression analysis was used to estimate a model of treatment received as a function of Medicare fees, controlling for other area economic factors, patient demographic and clinical characteristics, physician experience, and region. Principal Findings. In 1994, average Medicare fees (adjusted for the effects of modifiers and procedure mix) for mastectomy (MST) and breast conserving surgery (BCS) were $904 and $305, respectively. Holding other fees and factors fixed, a 10 percent increase in the BCS fee increased the odds of breast conserving surgery with radiation therapy relative to mastectomy to 1.34 ( p 5 0.02), while a 10 percent decrease in the MST fee increased the odds of breast conserving surgery with radiation therapy to 1.86 ( po0.01). Conclusions. Among older women with localized breast cancer, financial incentives appear to influence the use of mastectomy and breast conserving surgery with radiation therapy. This finding is consistent with the hypothesis that physicians are responsive to financial incentives when the alternative procedures have clinically equivalent outcomes and the patient's clinical condition does not dominate the treatment choice. We also find that the fee effects derived from this analysis of individual data with more precise measurement of both diagnosis and treatment are qualitatively similar to the results of the small-area analysis. This suggests that the earlier study was not severely affected by ecological bias or other data limitations inherent in Medicare claims data.

The repetitive nature and complexity of multiple medically important genes make them intractable to accurate analysis, despite the maturity of short-read sequencing, resulting in a gap in clinical applications of genome sequencing. The Genome in a Bottle Consortium has provided benchmark variant sets, but these excluded some medically relevant genes due to their repetitiveness or polymorphic complexity. In this study, we characterize 273 of these 395 challenging autosomal genes that have multiple implications for medical sequencing. This extended, curated benchmark reports over 17,000 SNVs, 3,600 INDELs, and 200 SVs each for GRCh37 and GRCh38. We show that false duplications in either GRCh37 or GRCh38 result in reference-specific, missed variants for short- and long-read technologies in medically important genes including CBS, CRYAA, and KCNE1. Our proposed solution improves variant recall in these genes from 8% to 100%. This benchmark will significantly improve the comprehensive characterization of these medically relevant genes and guide new method development.