Citations

ABSTRACTNext‐generation sequencing technologies have afforded unprecedented characterization of low‐frequency and rare genetic variation. Due to low power for single‐variant testing, aggregative methods are commonly used to combine observed rare variation within a single gene. Causal variation may also aggregate across multiple genes within relevant biomolecular pathways. Kernel‐machine regression and adaptive testing methods for aggregative rare‐variant association testing have been demonstrated to be powerful approaches for pathway‐level analysis, although these methods tend to be computationally intensive at high‐variant dimensionality and require access to complete data. An additional analytical issue in scans of large pathway definition sets is multiple testing correction. Gene set definitions may exhibit substantial genic overlap, and the impact of the resultant correlation in test statistics on Type I error rate control for large agnostic gene set scans has not been fully explored. Herein, we first outline a statistical strategy for aggregative rare‐variant analysis using component gene‐level linear kernel score test summary statistics as well as derive simple estimators of the effective number of tests for family‐wise error rate control. We then conduct extensive simulation studies to characterize the behavior of our approach relative to direct application of kernel and adaptive methods under a variety of conditions. We also apply our method to two case‐control studies, respectively, evaluating rare variation in hereditary prostate cancer and schizophrenia. Finally, we provide open‐source R code for public use to facilitate easy application of our methods to existing rare‐variant analysis results.

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Background and objectives Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. Design, setting, participants, & measurements In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. Results Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone formers and 110 controls developed hypertension. Median follow-up time was 7.8 years in stone formers and 9.6 years in controls. Stone formers were found to have a higher risk of hypertension compared with controls (hazard ratio, 1.50; 95% confidence interval, 1.18 to 1.92), even after adjusting for age, sex, body mass index, serum creatinine, CKD, diabetes, gout, coronary artery disease, dyslipidemia, tobacco use, and alcohol abuse (hazard ratio, 1.58; 95% confidence interval, 1.12 to 2.21). Results were similar after excluding patients who were ever on a thiazide diuretic (hazard ratio, 1.65; 95% confidence interval, 1.16 to 2.38). Stone composition, radiographic stone burden, number of subsequent stone events, and stone removal surgeries were not associated with hypertension ( P >0.05 for all). Conclusions The risk of hypertension was higher after the first symptomatic kidney stone event. However, kidney stone severity, type, and treatment did not associate with hypertension.

ObjectiveRhinoplasty, a surgical procedure that alters the shape or appearance of the nose while preserving or enhancing the nasal airway, ranks among the most commonly performed cosmetic procedures in the United States, with >200,000 procedures reported in 2014. While it is difficult to calculate the exact economic burden incurred by rhinoplasty patients following surgery with or without complications, the average rhinoplasty procedure typically exceeds $4000. The costs incurred due to complications, infections, or revision surgery may include the cost of long‐term antibiotics, hospitalization, or lost revenue from hours/days of missed work.The resultant psychological impact of rhinoplasty can also be significant. Furthermore, the health care burden from psychological pressures of nasal deformities/aesthetic shortcomings, surgical infections, surgical pain, side effects from antibiotics, and nasal packing materials must also be considered for these patients. Prior to this guideline, limited literature existed on standard care considerations for pre‐ and postsurgical management and for standard surgical practice to ensure optimal outcomes for patients undergoing rhinoplasty. The impetus for this guideline is to utilize current evidence‐based medicine practices and data to build unanimity regarding the peri‐ and postoperative strategies to maximize patient safety and to optimize surgical results for patients.PurposeThe primary purpose of this guideline is to provide evidence‐based recommendations for clinicians who either perform rhinoplasty or are involved in the care of a rhinoplasty candidate, as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The target audience is any clinician or individual, in any setting, involved in the management of these patients. The target patient population is all patients aged ≥15 years. The guideline is intended to focus on knowledge gaps, practice variations, and clinical concerns associated with this surgical procedure; it is not intended to be a comprehensive reference for improving nasal form and function after rhinoplasty. Recommendations in this guideline concerning education and counseling to the patient are also intended to include the caregiver if the patient is <18 years of age.Action StatementsThe Guideline Development Group made the following recommendations: (1) Clinicians should ask all patients seeking rhinoplasty about their motivations for surgery and their expectations for outcomes, should provide feedback on whether those expectations are a realistic goal of surgery, and should document this discussion in the medical record. (2) Clinicians should assess rhinoplasty candidates for comorbid conditions that could modify or contraindicate surgery, including obstructive sleep apnea, body dysmorphic disorder, bleeding disorders, or chronic use of topical vasoconstrictive intranasal drugs. (3) The surgeon, or the surgeon’s designee, should evaluate the rhinoplasty candidate for nasal airway obstruction during the preoperative assessment. (4) The surgeon, or the surgeon’s designee, should educate rhinoplasty candidates regarding what to expect after surgery, how surgery might affect the ability to breathe through the nose, potential complications of surgery, and the possible need for future nasal surgery. (5) The clinician, or the clinician’s designee, should counsel rhinoplasty candidates with documented obstructive sleep apnea about the impact of surgery on nasal airway obstruction and how obstructive sleep apnea might affect perioperative management. (6) The surgeon, or the surgeon’s designee, should educate rhinoplasty patients before surgery about strategies to manage discomfort after surgery. (7) Clinicians should document patients’ satisfaction with their nasal appearance and with their nasal function at a minimum of 12 months after rhinoplasty.The Guideline Development Group made recommendations against certain actions: (1) When a surgeon, or the surgeon’s designee, chooses to administer perioperative antibiotics for rhinoplasty, he or she should not routinely prescribe antibiotic therapy for a duration >24 hours after surgery. (2) Surgeons should not routinely place packing in the nasal cavity of rhinoplasty patients (with or without septoplasty) at the conclusion of surgery.The panel group made the following statement an option: (1) The surgeon, or the surgeon’s designee, may administer perioperative systemic steroids to the rhinoplasty patient.

ObjectiveRhinoplasty, a surgical procedure that alters the shape or appearance of the nose while preserving or enhancing the nasal airway, ranks among the most commonly performed cosmetic procedures in the United States, with >200,000 procedures reported in 2014. While it is difficult to calculate the exact economic burden incurred by rhinoplasty patients following surgery with or without complications, the average rhinoplasty procedure typically exceeds $4000. The costs incurred due to complications, infections, or revision surgery may include the cost of long‐term antibiotics, hospitalization, or lost revenue from hours/days of missed work.The resultant psychological impact of rhinoplasty can also be significant. Furthermore, the health care burden from psychological pressures of nasal deformities/aesthetic shortcomings, surgical infections, surgical pain, side effects from antibiotics, and nasal packing materials must also be considered for these patients. Prior to this guideline, limited literature existed on standard care considerations for pre‐ and postsurgical management and for standard surgical practice to ensure optimal outcomes for patients undergoing rhinoplasty. The impetus for this guideline is to utilize current evidence‐based medicine practices and data to build unanimity regarding the peri‐ and postoperative strategies to maximize patient safety and to optimize surgical results for patients.PurposeThe primary purpose of this guideline executive summary is to provide evidence‐based recommendations for clinicians who either perform rhinoplasty or are involved in the care of a rhinoplasty candidate, as well as to optimize patient care, promote effective diagnosis and therapy, and reduce harmful or unnecessary variations in care. The target audience is any clinician or individual, in any setting, involved in the management of these patients. The target patient population is all patients aged ≥15 years. The guideline is intended to focus on knowledge gaps, practice variations, and clinical concerns associated with this surgical procedure; it is not intended to be a comprehensive reference for improving nasal form and function after rhinoplasty. Recommendations in this guideline concerning education and counseling to the patient are intended to include the caregiver if the patient is <18 years of age.Action StatementsThe Guideline Development Group made the following recommendations: (1) Clinicians should ask all patients seeking rhinoplasty about their motivations for surgery and their expectations for outcomes, should provide feedback on whether those expectations are a realistic goal of surgery, and should document this discussion in the medical record. (2) Clinicians should assess rhinoplasty candidates for comorbid conditions that could modify or contraindicate surgery, including obstructive sleep apnea, body dysmorphic disorder, bleeding disorders, or chronic use of topical vasoconstrictive intranasal drugs. (3) The surgeon, or the surgeon’s designee, should evaluate the rhinoplasty candidate for nasal airway obstruction during the preoperative assessment. (4) The surgeon, or the surgeon’s designee, should educate rhinoplasty candidates regarding what to expect after surgery, how surgery might affect the ability to breathe through the nose, potential complications of surgery, and the possible need for future nasal surgery. (5) The clinician, or the clinician’s designee, should counsel rhinoplasty candidates with documented obstructive sleep apnea about the impact of surgery on nasal airway obstruction and how obstructive sleep apnea might affect perioperative management. (6) The surgeon, or the surgeon’s designee, should educate rhinoplasty patients before surgery about strategies to manage discomfort after surgery. (7) Clinicians should document patient satisfaction with their nasal appearance and with their nasal function at a minimum of 12 months after rhinoplasty.The guideline development group made recommendations against certain actions: (1) When a surgeon, or the surgeon’s designee, chooses to administer perioperative antibiotics for rhinoplasty, he or she should not routinely prescribe antibiotic therapy for a duration >24 hours after surgery. (2) Surgeons should not routinely place packing in the nasal cavity of rhinoplasty patients (with or without septoplasty) at the conclusion of surgery.The panel group made the following statement an option: (1) The surgeon, or the surgeon’s designee, may administer perioperative systemic steroids to the rhinoplasty patient.