Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

A National Study of State Policy for Fostering Gifted Program Evaluation: Content Analysis and Recommendation for Policy Development

Individual state policy plays a pivotal role in the policies and practices related to gifted education at the local level. While little is known about the frequency with which local school personnel evaluate their gifted and talented programs, the policy documents of 31 states include language to suggest that schools should conduct evaluations of their gifted and talented programs. In this study, a content analysis of high-level state policy documents was conducted to identify three main policy approaches for fostering local gifted program evaluation: (a) policies to initiate the development of sub-policies to guide program evaluation practice, (b) policies directly calling for schools to evaluate their gifted programs, and (c) policies that designate technical assistance services to support program evaluations. Findings from the content analysis also indicate that the majority of these policies lack the comprehensiveness Trochim describes in his theoretical work, the Evaluation Policy Wheel (EPW). For example, of the eight EPW components described as part of comprehensive evaluation policy, the most comprehensive of all the state evaluation policies examined in this study contained only 5 of the 8 policy components. In fact, the majority of the state policies (n = 20) contained less than 30% of the policy components from the EPW. ^ An illustrative case example was also included in this study to explore how researchers and policymakers might examine the alignment of state evaluation policy with other influential sources of program evaluation advice. In this study, the policies from one state were explored for their alignment with Patton\u27s Utilization-Focused Evaluation, the utilization strand from the Joint Committee\u27s Program Evaluation Standards, and the National Association for Gifted Children\u27s (NAGC) PreK-Grade 12 Gifted Programming Standards. This process resulted in an analytic framework through which evaluation policy may be examined for consistency with best practices recommendations, aiding in the illumination of sources of consistency as well as areas for further policy development or improvement.

Impact of Capital Gains Taxation on the Holding Period of Investments Under Different Tax Systems

An investment that is characterized by exit flexibility requires both decisions on investment and holding period. As selling an investment often leads to tax-liable capital gains and capital gains crucially depend on the duration of an investment we investigate the impact of capital gains taxation on the holding period under three different tax systems. In our analytical investigation we examine whether there is an optimal exit time and if there is no optimal exit time, what would be an appropriate time of sale. Moreover, we determine the worst exit time which should be avoided by investors. We find that while often an immediate sale is optimal longer holding periods may be beneficial under certain conditions. Beyond the well-known impact of the retention policy we clarify that the minimal holding period particularly depends on the degree of income and corporate tax integration. We find, e.g., a high retention rate to extend the minimum holding period under a shareholder relief tax system but is likely to accelerate sales under a classic corporate tax system. These results help to anticipate the economic implications of capital gains taxes on investment. Obviously, depending on the underlying tax system the after-tax profitability of long-term and sustainable investments is particularly affected by capital gains taxes. These results are interesting for both investors and tax politicians

Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort

Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR. Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census. Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P-value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P-value < 0.0001). Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure.People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window).Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p Background Methods Findings Interpretation Funding</p