Routinely reported ejection fraction and mortality in clinical practice: where does the nadir of risk lie?

Aims: We investigated the relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival in a large, heterogeneous clinical cohort. Methods and results: Physician-reported LVEF on 403 977 echocardiograms from 203 135 patients were linked to all-cause mortality using electronic health records (1998–2018) from US regional healthcare system. Cox proportional hazards regression was used for analyses while adjusting for many patient characteristics including age, sex, and relevant comorbidities. A dataset including 45 531 echocardiograms and 35 976 patients from New Zealand was used to provide independent validation of analyses. During follow-up of the US cohort, 46 258 (23%) patients who had undergone 108 578 (27%) echocardiograms died. Overall, adjusted hazard ratios (HR) for mortality showed a u-shaped relationship for LVEF with a nadir of risk at an LVEF of 60–65%, a HR of 1.71 [95% confidence interval (CI) 1.64–1.77] when ≥70% and a HR of 1.73 (95% CI 1.66–1.80) at LVEF of 35–40%. Similar relationships with a nadir at 60–65% were observed in the validation dataset as well as for each age group and both sexes. The results were similar after further adjustments for conditions associated with an elevated LVEF, including mitral regurgitation, increased wall thickness, and anaemia and when restricted to patients reported to have heart failure at the time of the echocardiogram. Conclusion: Deviation of LVEF from 60% to 65% is associated with poorer survival regardless of age, sex, or other relevant comorbidities such as heart failure. These results may herald the recognition of a new phenotype characterized by supra-normal LVEF

Association of Rare and Common Variation in the Lipoprotein Lipase Gene With Coronary Artery Disease.

IMPORTANCE: The activity of lipoprotein lipase (LPL) is the rate-determining step in clearing triglyceride-rich lipoproteins from the circulation. Mutations that damage the LPL gene (LPL) lead to lifelong deficiency in enzymatic activity and can provide insight into the relationship of LPL to human disease. OBJECTIVE: To determine whether rare and/or common variants in LPL are associated with early-onset coronary artery disease (CAD). DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, LPL was sequenced in 10 CAD case-control cohorts of the multinational Myocardial Infarction Genetics Consortium and a nested CAD case-control cohort of the Geisinger Health System DiscovEHR cohort between 2010 and 2015. Common variants were genotyped in up to 305 699 individuals of the Global Lipids Genetics Consortium and up to 120 600 individuals of the CARDIoGRAM Exome Consortium between 2012 and 2014. Study-specific estimates were pooled via meta-analysis. EXPOSURES: Rare damaging mutations in LPL included loss-of-function variants and missense variants annotated as pathogenic in a human genetics database or predicted to be damaging by computer prediction algorithms trained to identify mutations that impair protein function. Common variants in the LPL gene region included those independently associated with circulating triglyceride levels. MAIN OUTCOMES AND MEASURES: Circulating lipid levels and CAD. RESULTS: Among 46 891 individuals with LPL gene sequencing data available, the mean (SD) age was 50 (12.6) years and 51% were female. A total of 188 participants (0.40%; 95% CI, 0.35%-0.46%) carried a damaging mutation in LPL, including 105 of 32 646 control participants (0.32%) and 83 of 14 245 participants with early-onset CAD (0.58%). Compared with 46 703 noncarriers, the 188 heterozygous carriers of an LPL damaging mutation displayed higher plasma triglyceride levels (19.6 mg/dL; 95% CI, 4.6-34.6 mg/dL) and higher odds of CAD (odds ratio = 1.84; 95% CI, 1.35-2.51; P < .001). An analysis of 6 common LPL variants resulted in an odds ratio for CAD of 1.51 (95% CI, 1.39-1.64; P = 1.1 × 10-22) per 1-SD increase in triglycerides. CONCLUSIONS AND RELEVANCE: The presence of rare damaging mutations in LPL was significantly associated with higher triglyceride levels and presence of coronary artery disease. However, further research is needed to assess whether there are causal mechanisms by which heterozygous lipoprotein lipase deficiency could lead to coronary artery disease

Healthcare Utilization and Costs after Receiving a Positive BRCA1/2 Result from a Genomic Screening Program

Population genomic screening has been demonstrated to detect at-risk individuals who would not be clinically identified otherwise. However, there are concerns about the increased utilization of unnecessary services and the associated increase in costs. The objectives of this study are twofold: (1) determine whether there is a difference in healthcare utilization and costs following disclosure of a pathogenic/likely pathogenic (P/LP) BRCA1/2 variant via a genomic screening program, and (2) measure the post-disclosure uptake of National Comprehensive Cancer Network (NCCN) guideline-recommended risk management. We retrospectively reviewed electronic health record (EHR) and billing data from a female population of BRCA1/2 P/LP variant carriers without a personal history of breast or ovarian cancer enrolled in Geisinger&rsquo;s MyCode genomic screening program with at least a one-year post-disclosure observation period. We identified 59 women for the study cohort out of 50,726 MyCode participants. We found no statistically significant differences in inpatient and outpatient utilization and average total costs between one-year pre- and one-year post-disclosure periods ($18,821 vs.$19,359, p = 0.76). During the first year post-disclosure, 49.2% of women had a genetic counseling visit, 45.8% had a mammography and 32.2% had an MRI. The uptake of mastectomy and oophorectomy was 3.5% and 11.8%, respectively, and 5% of patients received chemoprevention

Electronic health record analysis identifies kidney disease as the leading risk factor for hospitalization in confirmed COVID-19 patients.

BackgroundEmpirical data on conditions that increase risk of coronavirus disease 2019 (COVID-19) progression are needed to identify high risk individuals. We performed a comprehensive quantitative assessment of pre-existing clinical phenotypes associated with COVID-19-related hospitalization.MethodsPhenome-wide association study (PheWAS) of SARS-CoV-2-positive patients from an integrated health system (Geisinger) with system-level outpatient/inpatient COVID-19 testing capacity and retrospective electronic health record (EHR) data to assess pre-COVID-19 pandemic clinical phenotypes associated with hospital admission (hospitalization).ResultsOf 12,971 individuals tested for SARS-CoV-2 with sufficient pre-COVID-19 pandemic EHR data at Geisinger, 1604 were SARS-CoV-2 positive and 354 required hospitalization. We identified 21 clinical phenotypes in 5 disease categories meeting phenome-wide significance (PConclusionsThis study provides quantitative estimates of the contribution of pre-existing clinical phenotypes to COVID-19 hospitalization and highlights kidney disorders as the strongest factors associated with hospitalization in an integrated US healthcare system

Electronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic Findings

Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods: 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results: 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion: pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain