Evaluating the performance of polygenic risk profiling across diverse ancestry populations in Parkinson's disease.

Objective: This study aims to address disparities in risk prediction by evaluating the performance of polygenic risk score (PRS) models using the 90 risk variants across 78 independent loci previously linked to Parkinson's disease (PD) risk across seven diverse ancestry populations. Methods: We conducted a multi-stage study, testing PRS models in predicting PD status across seven different ancestries applying three approaches: 1) PRS adjusted by gender and age; 2) PRS adjusted by gender, age and principal components (PCs); and 3) PRS adjusted by gender, age and percentage of population admixture. These models were built using the largest four population-specific summary statistics of PD risk to date (base data) and individual level data obtained from the Global Parkinson's Genetics Program (target data). We performed power calculations to estimate the minimum sample size required to conduct these analyses. A total of 91 PRS models were developed to investigate cumulative known genetic variation associated with PD risk and age of onset in a global context. Results: We observed marked heterogeneity in risk estimates across non-European ancestries, including East Asians, Central Asians, Latino/Admixed Americans, Africans, African admixed, and Ashkenazi Jewish populations. Risk allele patterns for the 90 risk variants yielded significant differences in directionality, frequency, and magnitude of effect. PRS did not improve in performance when predicting disease status using similar base and target data across multiple ancestries, demonstrating that cumulative PRS models based on current known risk are inherently biased towards European populations. We found that PRS models adjusted by percentage of admixture outperformed models that adjusted for conventional PCs in highly admixed populations. Overall, the clinical utility of our models in individually predicting PD status is limited in concordance with the estimates observed in European populations. Interpretation: This study represents the first comprehensive assessment of how PRS models predict PD risk and age at onset in a multi-ancestry fashion. Given the heterogeneity and distinct genetic architecture of PD across different populations, our assessment emphasizes the need for larger and diverse study cohorts of individual-level target data and well-powered ancestry-specific summary statistics. Our current understanding of PD status unraveled through GWAS in European populations is not generally applicable to other ancestries. Future studies should integrate clinical and *omics level data to enhance the accuracy and predictive power of PRS across diverse populations.

Copy Number Variants of Undetermined Significance Are Not Associated with Worse Clinical Outcomes in Hypoplastic Left Heart Syndrome.

OBJECTIVE: To determine the prevalence, spectrum, and prognostic significance of copy number variants of undetermined significance (cnVUS) seen on chromosomal microarray (CMA) in neonates with hypoplastic left heart syndrome (HLHS). STUDY DESIGN: Neonates with HLHS who presented to Texas Children's Hospital between June 2008 and December 2016 were identified. CMA results were abstracted and compared against copy number variations (CNVs) in ostensibly healthy individuals gathered from the literature. Findings were classified as normal, consistent with a known genetic disorder, or cnVUS. Survival was then compared using Kaplan-Meier analysis. Secondary outcomes included tracheostomy, feeding tube at discharge, cardiac arrest, and extracorporeal membrane oxygenation (ECMO). RESULTS: Our study cohort comprised 105 neonates with HLHS, including 70 (66.7%) with normal CMA results, 9 (8.6%) with findings consistent with a known genetic disorder, and 26 (24.7%) with a cnVUS. Six of the 26 (23.0%) neonates with a cnVUS had a variant that localized to a specific region of the genome seen in the healthy control population. One-year survival was 84.0% in patients with a cnVUS, 68.3% in those with normal CMA results, and 33.3% in those with a known genetic disorder (P = .003). There were no significant differences in secondary outcomes among the groups, although notably ECMO was used in 15.7% of patients with normal CMA and was not used in those with cnVUS and abnormal results (P = .038). CONCLUSIONS: Among children with HLHS, cnVUSs detected on CMA are common. The cnVUSs do not localize to specific regions of the genome, and are not associated with worse outcomes compared with normal CMA results.

Cardiac Arrest in Pediatric Patients Receiving Azithromycin.

OBJECTIVE: To compare outcomes of pediatric patients treated with azithromycin compared with penicillin or cephalosporin. We hypothesized that azithromycin use would not be associated with increased cardiac mortality in the pediatric population. STUDY DESIGN: Retrospective cohort study from the Pediatric Health Information System database between 2008 and 2012. Patients <19 years of age with a principal diagnosis of community-acquired pneumonia who received an antibiotic were included. Primary outcomes were cardiopulmonary resuscitation (CPR) and mortality. Secondary outcomes were ventricular arrhythmias incidences and readmission for ventricular arrhythmia. Statistical analysis was performed with the χ2 test. Multivariable analysis was performed to control for potential confounders among patient, event, and treatment characteristics. RESULTS: A total of 82 982 patients (54.3% males) met study criteria. Median age was 2.6 years (IQR 1.2-5.9 years) and median length of stay was 2 days (IQR 2-4 days). Azithromycin was used in 5039 (6.1%); penicillin or cephalosporin was used in 77 943 (93.9%). Overall prevalence of antibiotic-associated CPR was 0.14%. Patients receiving a macrolide antibiotic had a lower prevalence of CPR compared with patients receiving a penicillin or cephalosporin (0.04% vs 0.14%, P = .04), and there was no difference in mortality. Multivariable analysis did not find an association between macrolide use and CPR. CONCLUSIONS: In contrast to recent adult studies, among children hospitalized for community-acquired pneumonia, azithromycin use was not associated with a greater prevalence of cardiac arrest compared with penicillin or cephalosporin use.

Efficacy and safety of high-dose propranolol for the management of infant supraventricular tachyarrhythmias.

OBJECTIVE: To report our experience with high-dose propranolol monotherapy for prophylaxis and treatment of infant supraventricular arrhythmias (SAs). STUDY DESIGN: Patients <1 year of age initiated on enteral propranolol as inpatients for management of SA were identified during a 10-year time period from the Texas Children's Hospital pharmacy database. Patients were included if they received propranolol monotherapy for SA. Propranolol therapy was considered successful when patients were initiated and discharged on monotherapy, without documented recurrence of arrhythmia or requiring additional antiarrhythmic medication. Patients discharged on propranolol were followed as outpatients until therapy was discontinued or a year from initiation, whichever came first. RESULTS: A total of 287 patients met study criteria (59.2% male). Propranolol therapy was initiated at a median of 17 days of age (IQR 6-33 days) at a total daily dose of 3.6 ± 1.0 mg/kg/day. Propranolol was successful in controlling SA throughout the inpatient stay in 67.3% of patients. Only one patient experienced a clinically significant adverse event that required propranolol discontinuation. A multivariable logistic regression analysis identified the presence of congenital heart disease (OR 0.42, 95% CI 0.19-0.94, P = .04) and Wolff-Parkinson-White (OR 0.42, 95% CI 0.21-0.87, P = .01) as factors for nonsuccessful inpatient propranolol monotherapy. Of 190 patients discharged on propranolol monotherapy, 87.7% were recurrence free during follow-up. CONCLUSIONS: High-dose propranolol is safe and reasonably successful in the treatment of infant SA. Inpatient control may be a predictor of continued outpatient efficacy.

Use of a cardioselective beta-blocker for pediatric patients with prolonged QT syndrome.

The data on the efficacy of atenolol for long-QT syndrome (LQTS) are controversial. This study aimed to evaluate the efficacy of atenolol for pediatric patients with LQTS. A retrospective observational study investigating all patients who had LQTS treated with atenolol at two institutions was performed. The study identified 57 patients (23 boys and 34 girls) with a mean QT corrected for heart rate (QTc) of 521 ± 54 ms. The mean age of these patients at diagnosis was 9 ± 6 years. Their clinical manifestations included no symptoms (n = 33, 58%), ventricular tachycardia (n = 10, 18%), syncope (n = 6, 10%), resuscitated sudden cardiac death (n = 4, 7%), atrioventricular block (n = 2, 4%), and bradycardia or presyncope (n = 2, 3%). Of the 57 patients, 13 (22%) had a family history of sudden death. The follow-up period was 5.4 ± 4.5 years. Atenolol at a mean dose of 1.4 ± 0.5 mg/kg/day was administered twice a day for all the patients. The mean maximum heart rate was 132 ± 27 bpm on Holter monitors and 155 ± 16 bpm on exercise treadmill tests, with medication doses titrated up to achieve a maximum heart rate lower than 150 bpm on both tests. During the follow-up period, one patient died (noncompliant with atenolol at the time of death), and the remaining patients had no sudden cardiac death events. Four patients (8%) had recurrent ventricular arrhythmias, three of whom received an implantable cardioverter defibrillator (all symptomatic at the time of diagnosis). For three patients (6%), it was necessary to rotate to a different beta-blocker because of side effects or inadequate heart rate control. Atenolol administered twice daily constitutes a valid and effective alternative for the treatment of pediatric patients with LQTS.