Citations

Abstract Traditional Hardy–Weinberg equilibrium (HWE) tests (the χ2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in data sets composed of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and to evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence data sets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false-positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently among the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non–Small Cell Lung Cancer (NSCLC) address all aspects of management for NSCLC. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines regarding targeted therapies, immunotherapies, and their respective biomarkers.

AbstractBackgroundPulmonary vein isolation (PVI) with autonomic modulation may be more successful than PVI alone for atrial fibrillation (AF) ablation and may be signaled by changes in sinus rhythm heart rate (HR) post ablation. We sought to determine if a change in sinus rhythm HR predicted AF recurrence post PVI.MethodsPatients who underwent AF ablation from 2000 to 2011 were included if sinus rhythm was noted on ECG within 90 days pre and 7 days post ablation. Basic ECG interval and HR changes were analyzed and outcomes determined.ResultsA total of 1152 patients were identified (74.3% male, mean age 57 ± 11 years). Mean AF duration was 5.2 ± 5.3 years. Paroxysmal AF was noted in 712 (61.8%) of the patients. Mean EF was 61% ± 6%. Sinus rhythm HR was 61 ± 11 pre‐ablation and 76 ± 13 bpm post‐ablation (27% ± 24% increase, p < .001). The ability of relative HR change post‐ablation to predict AF recurrence was borderline (hazard ratio 0.65 [0.41–1.01], p = .067). With patients separated into quartiles based on the relative HR change, the upper quartile with the largest relative increase in HR had a significantly lower rate of AF recurrence compared to the lowest quartile following multi variable modeling (p = .038). There were significant changes in PR (171 ± 28 to 167 ± 30 ms) and QTc (424 ± 25 to 434 ± 29 ms) intervals (both p < .001) but these were not predictive of outcome.ConclusionRelative changes in HR post AF ablation correlates with AF recurrence. Further prospective studies are needed to confirm this relationship.

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel’s discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

ObjectiveThe degree to which various treatment modalities modify vestibular schwannoma (VS)–associated symptoms has received limited attention. The purpose of this study was to determine how different treatment modalities affect subjective symptoms in those presenting with VS.Study DesignProspective survey.SettingTertiary neurotology referral center.MethodsPatients with sporadic VS who received treatment at our institution were prospectively surveyed with a VS symptom questionnaire. Those who completed a baseline survey prior to treatment and at least 1 posttreatment survey were included. The prospective survey evaluated the severity of self‐reported symptoms (Likert scale, 1‐10), including tinnitus, dizziness or imbalance, headaches, and hearing loss.ResultsA total of 244 patients were included (mean age, 57 years). The mean duration of follow‐up was 2.1 years, and the median number of surveys completed was 2 (interquartile range, 1‐3). Seventy‐eight (32%) cases were managed with observation, 118 (48%) with microsurgery, and 48 (20%) with radiosurgery. Multivariable analyses revealed no statistically significant difference in the change in tinnitus (P =. 15), dizziness or imbalance (P = 0.66), or headaches (P =. 24) among treatment groups. Evaluation of clinically important differences demonstrated that microsurgery leads to significant bidirectional changes in headaches.ConclusionsLimited prospective data exist regarding the progression or resolution of subjective symptoms in those presenting with VS. This study suggests that tinnitus, dizziness or imbalance, and headaches are unlikely to be significantly modified by treatment modality and generally should not be used to direct treatment choice.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Objectives/Hypothesis To describe the pre‐implant audiometric profile of adult cochlear implant (CI) recipients to investigate whether current binaural candidacy requirements prevent access to patients who could benefit from CI. Study Design Retrospective case series. Methods Retrospective review from 2016 to 2018 evaluating preoperative pure‐tone thresholds and speech perception scores in the ipsilateral and contralateral ear. Results A total of 252 adult CI recipients undergoing 270 implants were identified. Median age at time of implantation was 70.5 years (IQR 61.3–78.3) for those undergoing unilateral implantation and 59.0 (IQR 48.0–72.3) for those undergoing bilateral implantation ( P < .01). For unilateral implantation, median pre‐implantation speech perception performance in the ear to be implanted was 8.0% (IQR 0%–26.0%) for CNC word scores, and 9.0% (IQR 0%–34.0%) for AzBio sentence scores in quiet. Median speech perception performance in the contralateral ear was 36.0% (IQR 14.0%–60.0%) on CNC word scores, and 48.5% (IQR 17.5%–76.0%) on AzBio sentence tests. Speech perception scores were significantly different between ears for word and sentence tests ( P < .01). Patients older than age 65 were significantly less likely to undergo bilateral implantation ( P = .03). Conclusions Adult CI recipients exhibit substantially poorer pre‐implant speech perception scores than the commonly utilized ipsilateral qualifying threshold of 50% on sentence testing. Yet, existing insurance paradigms limit patients by excessively stringent binaural best‐aided requirements. This limitation likely leads to worse device performance as patients often wait years for their binaural hearing to qualify while their ear to be implanted potentially experiences an unnecessarily extended duration of deafness. Older patients also experience a unique delay in referral for cochlear implantation. Level of Evidence 3‐ Retrospective review Laryngoscope , 131:E2007–E2012, 2021

Background: Thromboelastography (TEG®) is used across a wide range of clinical settings to identify patients at risk for thrombosis and coagulopathic bleeding and may be a useful diagnostic tool to guide antithrombotic treatment in patients with COVID-19. Hypothesis: TEG® identifies symptom progression in COVID -19 patients, particularly in the high-risk minority population known to have worse clinical outcomes. Methods: Whole blood from African American and Hispanic hospitalized COVID positive (n=22) and negative outpatients (n=24) was analyzed using point-of-care TEG®6s (Haemonetics, Corp). TEG® parameters including clot initiation (R), fibrin clot strength (FCS), platelet-fibrin clot strength (PFCS) and clot lysis (LY30) were compared across disease severity groups (table). Routine labs including D-Dimer, C-reactive protein (CRP), ferritin, and procalcitonin were also collected. Results: Ninety- five percent of COVID positive patients had at least one co-morbidity with the incidence of hypertension (73%), diabetes (55%), and obesity (45%) being the most frequent. R time was more rapid, and FCS and PFCS was significantly higher in COVID positive as compared to negative groups (p<0.03). A stepwise increase in FCS and PFCS was observed with worsening respiratory function (table). Similarly, D-Dimer, CRP, ferritin, and procalcitonin levels were highest in patients receiving ventilator support. No differences were observed in clot lysis between the groups despite elevated D-Dimer levels. Conclusion: We have demonstrated that TEG®6s can identify a prothrombotic phenotype characterized by rapid clot initiation and increased fibrin and platelet-fibrin clot strength in a minority population with COVID-19. Future studies are warranted implementing the TEG6s® in clinical trials to personalize antithrombotic therapy in COVID-19 and improve outcomes.

Background: Previous cross-sectional studies analyzing quality of life (QOL) outcomes in patients with sporadic vestibular schwannoma (VS) have shown surprisingly little difference among treatment modalities. To date, there is limited prospective QOL outcome data available comparing baseline to posttreatment scores. Study Design: Prospective longitudinal study using the disease-specific Penn Acoustic Neuroma Quality of Life (PANQOL) scale. Setting: Large academic skull base center. Patients: Patients diagnosed with unilateral VS who completed a baseline survey before treatment and at least one posttreatment survey. Main Outcome Measures: Change in PANQOL scores from baseline to most recent survey. Results: A total of 244 patients were studied, including 78 (32%) who elected observation, 118 (48%) microsurgery, and 48 (20%) stereotactic radiosurgery. Patients who underwent microsurgery were younger (p < 0.001) and had larger tumors (p < 0.001) than those who underwent observation or radiosurgery; there was no significant difference in duration of follow-up among management groups (mean 2.1 yrs; p = 0.28). When comparing the total PANQOL score at baseline to the most recent survey, the net change was only –1.1, –0.1, and 0.3 points on a 100-point scale for observation, microsurgery, and radiosurgery, respectively (p = 0.89). After multivariable adjustment for baseline features, there were no statistically significant changes when comparing baseline to most recent scores within each management group for facial function, general health, balance, hearing loss, energy, and pain domains or total score. However, the microsurgical group experienced a 10.8-point improvement (p = 0.002) in anxiety following treatment, compared with 1.5 (p = 0.73) and 5.3 (p = 0.31) for observation and radiosurgery, respectively. Conclusions: In this prospective longitudinal study investigating differences in QOL outcomes among VS treatment groups using the disease-specific PANQOL instrument, treatment did not modify QOL in most domains. Microsurgery may confer an advantage with regard to patient anxiety, presumably relating to the psychological benefit of “cure” from having the tumor removed.