Detection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome.

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this haplotype, which we confirm to carry p.Asp76Asn. Referral and non-referral carriers have prolonged QT interval corrected for heart rate (QTc) compared to controls, and, among carriers, the QTc polygenic score is independently associated with QTc prolongation. Thus, our innovative analysis of shared chromosomal segments identifies undiagnosed cases of genetic disease and refines the understanding of LQT5 penetrance and phenotype.

Detection of distant relatedness in biobanks for identification of undiagnosed carriers of a Mendelian disease variant: application to Long QT Syndrome.

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we developed a generalizable method of genotype inference based on distant relatedness and deployed this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identified 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncovered recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identified 22 additional subjects sharing this haplotype, subsequently confirmed to carry p.Asp76Asn. Referral and non-referral carriers had prolonged QTc compared to controls, and, among carriers, QTc polygenic score additively associated with QTc prolongation. Thus, our novel analysis of shared chromosomal segments identified undiagnosed cases of genetic disease and refined the understanding of LQT5 penetrance and phenotype.

Happier countries, longer lives: an ecological study on the relationship between subjective sense of well-being and life expectancy.

The relationship between sense of well-being and longevity is not well-established across populations of varying levels of socioeconomic status. We sought to examine the relationship between happiness, or subjective sense of well-being and life expectancy using data from 151 countries. This analysis is based on the 2012 Happy Planet Index project conducted by the Center of Well-Being of the New Economics Foundation, based in the United Kingdom. Well-being data for each country were taken from responses to the 'Ladder of Life' question in the 2012 Gallup World Poll in which participants were asked to rate their quality of life on a scale from 1 (worst possible life) to 10 (best possible life). Life expectancy and gross domestic product data were taken from the 2011 United Nations records. Ecological footprint data were taken from Global Footprint Network records. Subjective sense of well-being was highly correlated with life expectancy (Pearson correlation r = 0.71, p < 0.0001). In a multivariable linear regression model adjusted for gross domestic product, ecological footprint, and population, each 1 unit of the well-being scale was associated with an increase in life expectancy of 4.0 years (95% confidence interval = 2.7-5.3). In conclusion, better sense of well-being has a strong relationship with life expectancy regardless of economic status or population size, suggesting that governments should foster happiness in order to support long-living populations.

Feasibility of Using Mobile ECG Recording Technology to Detect Atrial Fibrillation in Low-Resource Settings.

BACKGROUND: Screening for atrial fibrillation (AF), a major risk factor for stroke that is on the rise in Africa, is becoming increasingly critical. OBJECTIVES: This study sought to examine the feasibility of using mobile electrocardiogram (ECG) recording technology to detect AF. METHODS: In this prospective observational study, we used a mobile ECG recorder to screen 50 African adults (66% women; mean age 54.3 ± 20.5 years) attending Kijabe Hospital (Kijabe, Kenya). Five hospital health providers involved in this study's data collection process also completed a self-administered survey to obtain information on their access to the Internet and mobile devices, both factors necessary to implement ECG mobile technology. Outcome measures included feasibility (completion of the study and recruitment of the patients on the planned study time frame) and the yield of the screening by the mobile ECG technology (ability to detect previously undiagnosed AF). RESULTS: Patients were recruited in a 2-week period as planned; only 1 of the 51 patients approached refused to participate (98% acceptance rate). All of the 50 patients who agreed to participate completed the test and produced readable ECGs (100% study completion rate). ECG tracings of 4 of the 50 patients who completed the study showed AF (8% AF yield), and none had been previously diagnosed with AF. When asked about continuous access to Internet and personal mobile devices, almost all of the health care providers surveyed answered affirmatively. CONCLUSIONS: Using mobile ECG technology in screening for AF in low-resource settings is feasible, and can detect a significant proportion of AF cases that will otherwise go undiagnosed. Further study is needed to examine the cost-effectiveness of this approach for detection of AF and its effect on reducing the risk of stroke in developing countries.