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Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.

The Ross procedure is an excellent operation to treat children and adults with aortic valve disease. Compared to prosthetic aortic valve replacement, it provides important clinical benefits in terms of survival, hemodynamics, freedom from valve-related complications, and durability, especially in women of childbearing age. However, the Ross procedure is a longer and technically more challenging operation. As a result, the choice of procedure should be driven by patient anatomy and clinical characteristics. This highlights the importance of concentrating care in Ross reference centers where surgical expertise and experience are present to ensure patient safety and long-term effectiveness of the operation. This manuscript reviews the major and relative contraindications to the Ross procedure. [ABSTRACT FROM AUTHOR]

Background and Aim: The opioid epidemic has become a major public health crisis in recent years. Discharge opioid prescription following cardiac surgery has been associated with opioid use disorder; however, ideal practices remain unclear. Our aim was to examine current practices in discharge opioid prescription among cardiac surgeons and trainees. Methods: A survey instrument with open‐ and closed‐ended questions, developed through a 3‐round Delphi method, was circulated to cardiac surgeons and trainees via the Canadian Society of Cardiac Surgeons. Survey questions focused on routine prescription practices including type, dosage and duration. Respondents were also asked about their perceptions of current education and guidelines surrounding opioid medication. Results: Eighty‐one percent of respondents reported prescribing opioids at discharge following routine sternotomy‐based procedures, however, there remained significant variability in the type and dose of medication prescribed. The median (interquartile range) number of pills prescribed was 30 (20‐30) with a median total dose of 135 (113‐200) Morphine Milligram Equivalents. Informal teaching was the most commonly reported primary influence on prescribing habits and a lack of formal education regarding opioid prescription was associated with a higher number of pills prescribed. A majority of respondents (91%) felt that there would be value in establishing practice guidelines for opioid prescription following cardiac surgery. Conclusions: Significant variability exists with respect to routine opioid prescription at discharge following cardiac surgery. Education has come predominantly from informal sources and there is a desire for guidelines. Standardization in this area may have a role in combatting the opioid epidemic. [ABSTRACT FROM AUTHOR]

Aortic valve replacement in children represents an important challenge. Concerns regarding pulmonary autograft and homograft longevity requiring reoperations are well recognized. Very long-term outcomes after the Ross procedure are still unknown. We reviewed our experience with the Ross procedure, aiming to define very long-term survival rate and freedom from reintervention. This was a single-center retrospective cohort including 63 consecutive children who underwent the Ross procedure. Median follow-up duration was 20.5 years. Time-related events were assessed using Kaplan-Meier estimator. There were 51 (81%) boys, mean age 10.1 ± 5.8 years. Isolated aortic stenosis was the most common diagnosis (n = 29, 46%) and 34 (54%) patients previously underwent cardiac surgery. There was 1 (1.6%) in-hospital death. Overall survival at 5, 15, and 25 years was 96.7%, 94.4%, and 94.4%, respectively. Freedom from any autograft-related reintervention was 98.1%, 86.4%, and 61.2% at 5, 15, and 25 years, respectively. Fifteen (24%) patients underwent autograft reoperations. Among them, 10 (67%) patients underwent valve-sparing autograft reoperation. Freedom from any pulmonary conduit reintervention was 93.2%, 58.2%, and 28.3% at 5, 15, and 25 years, respectively. Thirty (46.6%) patients underwent conduit reintervention (8 percutaneous, 22 surgical replacements). The pediatric Ross procedure is associated with excellent long-term survival. Ross-related reinterventions are more than twice as common on the pulmonary homograft than on the autograft. [ABSTRACT FROM AUTHOR]

We propose a new method, G-REMLadp, to estimate the phenotypic variance explained by parent-of-origin effects (POEs) across the genome. Our method uses restricted maximum likelihood analysis of genome-wide genetic relatedness matrices based on individuals' phased genotypes. Genome-wide SNP data from parent child duos or trios is required to obtain relatedness matrices indexing the parental origin of offspring alleles, as well as offspring phenotype data to partition the trait variation into variance components. To calibrate the power of G-REMLadp to detect non-null POEs when they are present, we provide an analytic approximation derived from Haseman-Elston regression. We also used simulated data to quantify the power and Type I Error rates of G-REMLadp, as well as the sensitivity of its variance component estimates to violations of underlying assumptions. We subsequently applied G-REMLadp to 36 phenotypes in a sample of individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We found that the method does not seem to be inherently biased in estimating variance due to POEs, and that substantial correlation between parental genotypes is necessary to generate biased estimates. Our empirical results, power calculations and simulations indicate that sample sizes over 10000 unrelated parent-offspring duos will be necessary to detect POEs explaining < 10% of the variance with moderate power. We conclude that POEs tagged by our genetic relationship matrices are unlikely to explain large proportions of the phenotypic variance (i.e. > 15%) for the 36 traits that we have examined. [ABSTRACT FROM AUTHOR]

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously. Results: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies. [ABSTRACT FROM AUTHOR]

Motivation: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients (r2) of the variants. However, haplotypes rather than pairwise r2, are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel. Results: Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N<2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome metaanalyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization). [ABSTRACT FROM AUTHOR]

The Lasso is a shrinkage regression method that is widely used for variable selection in statistical genetics. Commonly, K-fold cross-validation is used to fit a Lasso model. This is sometimes followed by using bootstrap confidence intervals to improve precision in the resulting variable selections. Nesting cross-validation within bootstrapping could provide further improvements in precision, but this has not been investigated systematically. We performed simulation studies of Lasso variable selection precision (VSP) with and without nesting cross-validation within bootstrapping. Data were simulated to represent genomic data under a polygenic model as well as under a model with effect sizes representative of typical GWAS results. We compared these approaches to each other as well as to software defaults for the Lasso. Nested cross-validation had the most precise variable selection at small effect sizes. At larger effect sizes, there was no advantage to nesting. We illustrated the nested approach with empirical data comprising SNPs and SNP-SNP interactions from the most significant SNPs in a GWAS of borderline personality symptoms. In the empirical example, we found that the default Lasso selected low-reliability SNPs and interactions which were excluded by bootstrapping. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that fish consumption can restrict weight gain. However, little is known about how fish consumption affects gestational weight gain (GWG), and whether this relationship depends on genetic makeup. Objective: To examine the association between fish consumption and GWG, and whether this relationship is dependent on molecular genetic predisposition to obesity. Design: A nested case-cohort study based on the Danish National Birth Cohort (DNBC) sampling the most obese women (n = 990) and a random sample of the remaining participants (n = 1,128). Replication of statistically significant findings was attempted in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 4,841). We included 32 body mass index (BMI) associated single nucleotide polymorphisms (SNPs) and 5 SNPs found associated with GWG. BMI associated SNPs were combined in a genetic risk score (GRS). Associations between consumption of fish, GRS or individual variants and GWG were analysed, and interactions between fish and the GRS or individual variants were examined. Results: In the DNBC, each portion/week (150 g) of fatty fish was associated with a higher GWG of 0.58 kg (95% CI: 0.16, 0.99, P<0.01). For total fish and lean fish, similar patterns were observed, but these associations were not statistically significant. We found no association between GRS and GWG, and no interactions between GRS and dietary fish on GWG. However, we found an interaction between the PPARG Pro12Ala variant and dietary fish. Each additional Pro12Ala G-allele was associated with a GWG of -0.83 kg (95% CI: -1.29, -0.37, P<0.01) per portion/week of dietary fish, with the same pattern for both lean and fatty fish. In ALSPAC, we were unable to replicate these findings. Conclusion: We found no consistent evidence of association between fish consumption and GWG, and our results indicate that the association between dietary fish and GWG has little or no dependency on GRS or individual SNPs. [ABSTRACT FROM AUTHOR]

Epistasis is a growing area of research in genome-wide studies, but the differences between alternative definitions of epistasis remain a source of confusion for many researchers. One problem is that models for epistasis are presented in a number of formats, some of which have difficult-to-interpret parameters. In addition, the relation between the different models is rarely explained. Existing software for testing epistatic interactions between single-nucleotide polymorphisms (SNPs) does not provide the flexibility to compare the available model parameterizations. For that reason we have developed an R package for investigating epistatic and penetrance models, Epi2Loc, to aid users who wish to easily compare, interpret, and utilize models for two-locus epistatic interactions. Epi2Loc facilitates research on SNP–SNP interactions by allowing the R user to easily convert between common parametric forms for two-locus interactions, generate data for simulation studies, and perform power analyses for the selected model with a continuous or dichotomous phenotype. The usefulness of the package for model interpretation and power analysis is illustrated using data on rheumatoid arthritis. [ABSTRACT FROM PUBLISHER]

Introduction: Aortic valve replacement in children and infants poses an important clinical challenge. The Ross procedure offers advantages such as growth potential and low thrombogenicity. Concerns regarding pulmonary autograft and homograft longevity as well as subsequent reoperations are well recognized. We reviewed our experience with the Ross procedure with the aim of defining survival rate and freedom from reintervention. Methods: This is a single-center retrospective cohort including 63 consecutive children who underwent the Ross procedure. The first Ross procedure was performed in 1990. Complete postoperative clinical and echocardiographic evaluation was obtained. Long-term survival was assessed using Kaplan-Meier estimator. Results: There were 51 males (81%) and mean age at surgery was 10.1 (+/- 5.8) years. Isolated aortic stenosis was the most common diagnosis and found in 28 (44.4%) patients. Median follow-up duration was 20.5 years and ranged up to 26.9 years. There was one (1.6%) hospital death. Survival at 5, 15 and 25 years was 96.6%, 94.4% and 94.4%, respectively. Freedom from autograft-related reintervention was 98.1%, 88.9% and 66.8% at 5, 15 and 25 years, respectively. Twelve patients underwent reoperations on the autograft and there was no post-operative death. Among these patients, 7 (58.3%) patients underwent valve-sparing autograft reoperation. Reintervention on the pulmonary homograft was performed on 29 (46.0%) patients. Freedom from homograft-related reintervention was 93.2%, 58.2% and 29.8% at 5, 15 and 25 years, respectively. Conclusions: The Ross procedure in children is associated with excellent long-term outcomes. Ross-related reinterventions are more than twice as common on the pulmonary homograft than autograft. [ABSTRACT FROM AUTHOR]

An abstract of the article "Stability Selection for Penalized Canonical Correlation Analysis," by Charles Laurin is presented.

Genome-wide association studies of psychiatric disorders have been criticized for their lack of explaining a considerable proportion of the heritability established in twin and family studies. Genome-wide association studies of major depressive disorder in particular have so far been unsuccessful in detecting genome-wide significant single nucleotide polymorphisms (SNPs). Using two recently proposed methods designed to estimate the heritability of a phenotype that is attributable to genome-wide SNPs, we show that SNPs on current platforms contain substantial information concerning the additive genetic variance of major depressive disorder. To assess the consistency of these two methods, we analyzed four other complex phenotypes from different domains. The pattern of results is consistent with estimates of heritability obtained in twin studies carried out in the same population. [Copyright &y& Elsevier]

Aortic root reconstruction operations have undergone substantial evolution with technical modifications, expanding indications, and the need for increasingly complex decision-making. The purpose of this state-of-the-art review is to detail our approach to contemporary aortic root reconstruction operations. First, we review the evolution of root reconstruction procedures over the years and discuss the approach to the aortic root patient for lifetime management of aneurysm and valvular disease in the modern context of management options. We also discuss state-of-the art technical considerations of valve-sparing root replacement, variations of the Ross operation, aortic valve repair principles and challenges in special populations, and considerations for complication-free coronary button reconstruction. We also discuss root reconstruction in high-risk subpopulations including acute type A aortic dissection, congenital, and reoperative patients. We briefly highlight future directions in transcatheter root replacement as well as the outlook for the next generation of aortic root surgeons., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.W.C. is supported as the Ray and Elliott Chair in Surgical Innovation and has received speakers honoraria from Medtronic, Edwards Lifesciences, Terumo Aortic, and Artivion.

The Ross procedure is an excellent operation to treat children and adults with aortic valve disease. Compared to prosthetic aortic valve replacement, it provides important clinical benefits in terms of survival, hemodynamics, freedom from valve-related complications, and durability, especially in women of childbearing age. However, the Ross procedure is a longer and technically more challenging operation. As a result, the choice of procedure should be driven by patient anatomy and clinical characteristics. This highlights the importance of concentrating care in Ross reference centers where surgical expertise and experience are present to ensure patient safety and long-term effectiveness of the operation. This manuscript reviews the major and relative contraindications to the Ross procedure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: This study reports on the main criteria used by Canadian cardiac surgery residency program committees (RPCs) to select applicants and the perceptions of Canadian medical students interested in cardiac surgery., Methods: A 50-question online survey was sent to all 12 Canadian cardiac surgery RPCs. A similar 52-question online survey targeted at Canadian medical students interested in applying to cardiac surgery residency programs was distributed. Data from both surveys were analyzed using descriptive statistics., Results: A total of 62% of all cardiac surgery RPC members (66 of 106) participated, including committee members from all 12 programs (range: 1-12 members per program; 9%-100% response rate per program) and 67% of program directors (8 of 12). Forty-one Canadian medical students (22 pre-clerks [54%], 2 MD/PhD students [5%], and 17 clinical clerks [41%]) participated. Committee members considered the following criteria to be most important when selecting candidates: on-service clinical performance, the interview, quality of reference letters from cardiac surgeons, and completing a rotation at the target program's institution. In contrast, the following criteria relating to the candidate were considered to be less important: wanting to practice in the city or province of training, having a connection to the program location, and personally knowing committee members. Medical students' perceptions were concordant regarding what factors are the most important but they overestimated the influence of non-clinical factors and research productivity in increasing their competitiveness., Conclusion: Canadian cardiac surgery residency programs seek applicants who demonstrate clinical excellence, as assessed by surgical rotations and reference letters from colleagues, and strong interview performance., (© 2022 The Authors.)

Genomic imprinting is an epigenetic mechanism leading to parent-of-origin silencing of alleles. So far, the precise number of imprinted regions in humans is uncertain. In this study, we leveraged genome-wide DNA methylation in whole blood measured longitudinally at three time points (birth, childhood and adolescence) and genome-wide association studies (GWAS) data in 740 mother-child duos from the Avon Longitudinal Study of parents and children to identify candidate imprinted loci. We reasoned that cis-meQTLs at genomic regions that were imprinted would show strong evidence of parent-of-origin associations with DNA methylation, enabling the detection of imprinted regions. Using this approach, we identified genome-wide significant cis-meQTLs that exhibited parent-of-origin effects (POEs) at 82 loci, 34 novel and 48 regions previously implicated in imprinting (3.7-10

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies., Competing Interests: GH, JZ, BE, KW, VH, DB, CL, SB, JB, RL, VT, JY, HS, NT, DE, CR, RM, GD, TG, PH No competing interests declared, (© 2018, Hemani et al.)

Motivation: LD score regression is a reliable and efficient method of using genome-wide association study (GWAS) summary-level results data to estimate the SNP heritability of complex traits and diseases, partition this heritability into functional categories, and estimate the genetic correlation between different phenotypes. Because the method relies on summary level results data, LD score regression is computationally tractable even for very large sample sizes. However, publicly available GWAS summary-level data are typically stored in different databases and have different formats, making it difficult to apply LD score regression to estimate genetic correlations across many different traits simultaneously., Results: In this manuscript, we describe LD Hub - a centralized database of summary-level GWAS results for 173 diseases/traits from different publicly available resources/consortia and a web interface that automates the LD score regression analysis pipeline. To demonstrate functionality and validate our software, we replicated previously reported LD score regression analyses of 49 traits/diseases using LD Hub; and estimated SNP heritability and the genetic correlation across the different phenotypes. We also present new results obtained by uploading a recent atopic dermatitis GWAS meta-analysis to examine the genetic correlation between the condition and other potentially related traits. In response to the growing availability of publicly accessible GWAS summary-level results data, our database and the accompanying web interface will ensure maximal uptake of the LD score regression methodology, provide a useful database for the public dissemination of GWAS results, and provide a method for easily screening hundreds of traits for overlapping genetic aetiologies., Availability and Implementation: The web interface and instructions for using LD Hub are available at http://ldsc.broadinstitute.org/ CONTACT: jie.zheng@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Motivation: Fine mapping is a widely used approach for identifying the causal variant(s) at disease-associated loci. Standard methods (e.g. multiple regression) require individual level genotypes. Recent fine mapping methods using summary-level data require the pairwise correlation coefficients ([Formula: see text]) of the variants. However, haplotypes rather than pairwise [Formula: see text], are the true biological representation of linkage disequilibrium (LD) among multiple loci. In this article, we present an empirical iterative method, HAPlotype Regional Association analysis Program (HAPRAP), that enables fine mapping using summary statistics and haplotype information from an individual-level reference panel., Results: Simulations with individual-level genotypes show that the results of HAPRAP and multiple regression are highly consistent. In simulation with summary-level data, we demonstrate that HAPRAP is less sensitive to poor LD estimates. In a parametric simulation using Genetic Investigation of ANthropometric Traits height data, HAPRAP performs well with a small training sample size (N < 2000) while other methods become suboptimal. Moreover, HAPRAP's performance is not affected substantially by single nucleotide polymorphisms (SNPs) with low minor allele frequencies. We applied the method to existing quantitative trait and binary outcome meta-analyses (human height, QTc interval and gallbladder disease); all previous reported association signals were replicated and two additional variants were independently associated with human height. Due to the growing availability of summary level data, the value of HAPRAP is likely to increase markedly for future analyses (e.g. functional prediction and identification of instruments for Mendelian randomization)., Availability and Implementation: The HAPRAP package and documentation are available at http://apps.biocompute.org.uk/haprap/ CONTACT: : jie.zheng@bristol.ac.uk or tom.gaunt@bristol.ac.ukSupplementary information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press.)

Background: The repair of anterior mitral leaflet prolapse is known to be challenging. Hence, the study aim was to compare the mid-term results of anterior leaflet prolapse (ALP) using chordal transposition with results obtained using chordal replacement with expanded polytetrafluoroethylene (ePTFE) sutures., Methods: Between 1999 and 2012, a total of 96 consecutive patients (mean age 62 years) with ALP underwent mitral valve repair at the authors' institution. Surgery involved either chordal transposition from the posterior to the anterior leaflet (n = 67), or chordal replacement using ePTFE sutures (n = 29). Clinical, operative and follow up data were recorded prospectively for each patient. The follow up was 100% complete (mean 3.4 years; range 0 to 12.9 years)., Results: Mitral valve repair was accomplished in all patients, with no operative mortality. The durations of cardiopulmonary bypass and aortic cross-clamp were significantly longer in the chordal replacement group. Actuarial overall survival at one, five and 10 years was 95 ± 3%, 87 ± 5% and 82 ± 7% versus 89 ± 6%, 89 ± 6% and 89 ± 6% in the chordal transposition and chordal replacement groups, respectively (p = 0.84). Freedom from reoperation in the two groups at five years was 95 ± 3% and 91 ± 7%, respectively (p = 0.24). The recurrence of moderate or severe mitral regurgitation (MR) (grade ≤2+) and of severe (grade ≤3+) MR was significantly higher in patients who underwent chordal replacement compared to chordal transposition (p = 0.04 and p = 0.01, respectively)., Conclusions: Provided that chordal quality is preserved, chordal transposition is easier and quicker to achieve for ALP repair, and is also durable in the mid term. Chordal replacement offers a satisfying durability even if the recurrence of severe MR appears to be higher. Preferably, both surgical techniques should be mastered to allow valve repair when anatomic conditions prevent chordal transposition.