Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality

EBioMedicine · 2022 · 24 citations

• Biology
• Immunology
• Genetics

BACKGROUND: Severe COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. METHODS: We developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population. FINDINGS: The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age. INTERPRETATION: Short HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Genetic diversity fuels gene discovery for tobacco and alcohol use

Nature · 2022 · 504 citations

• Biology
• Genetics
• Evolutionary biology

. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

Beyond the Imitation Game: Quantifying and extrapolating the capabilities of language models

arXiv (Cornell University) · 2022 · 548 citations

• Computer Science
• Artificial Intelligence
• Computer Science

Language models demonstrate both quantitative improvement and new qualitative capabilities with increasing scale. Despite their potentially transformative impact, these new capabilities are as yet poorly characterized. In order to inform future research, prepare for disruptive new model capabilities, and ameliorate socially harmful effects, it is vital that we understand the present and near-future capabilities and limitations of language models. To address this challenge, we introduce the Beyond the Imitation Game benchmark (BIG-bench). BIG-bench currently consists of 204 tasks, contributed by 450 authors across 132 institutions. Task topics are diverse, drawing problems from linguistics, childhood development, math, common-sense reasoning, biology, physics, social bias, software development, and beyond. BIG-bench focuses on tasks that are believed to be beyond the capabilities of current language models. We evaluate the behavior of OpenAI's GPT models, Google-internal dense transformer architectures, and Switch-style sparse transformers on BIG-bench, across model sizes spanning millions to hundreds of billions of parameters. In addition, a team of human expert raters performed all tasks in order to provide a strong baseline. Findings include: model performance and calibration both improve with scale, but are poor in absolute terms (and when compared with rater performance); performance is remarkably similar across model classes, though with benefits from sparsity; tasks that improve gradually and predictably commonly involve a large knowledge or memorization component, whereas tasks that exhibit "breakthrough" behavior at a critical scale often involve multiple steps or components, or brittle metrics; social bias typically increases with scale in settings with ambiguous context, but this can be improved with prompting.

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Nature · 2021 · 2261 citations

• Computer Science
• Biology
• Genetics

. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Nature Genetics · 2020 · 236 citations

• Biology
• Genetics
• Internal medicine

), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Sex-Specific Associations of Cardiovascular Risk Factors and Biomarkers With Incident Heart Failure

Journal of the American College of Cardiology · 2020 · 103 citations

• Medicine
• Internal medicine
• Cardiology

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001). CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

Protein Biomarkers and Risk of Atrial Fibrillation

Circulation Arrhythmia and Electrophysiology · 2020 · 59 citations

• Medicine
• Internal medicine
• Cardiology

BACKGROUND: Identification of protein biomarkers associated with incident atrial fibrillation (AF) may improve the understanding of the pathophysiology, risk prediction, and development of new therapeutics for AF. We examined the associations between 85 protein biomarkers and incident AF. METHODS: We included participants ≥50 years of age from the FHS (Framingham Heart Study) Offspring and Third Generation cohorts, who had 85 fasting plasma proteins measured using Luminex xMAP platform. Hazard ratios (per 1 SD increment of rank-normalized biomarker [hazard ratio]) and 95% CIs for incident AF were calculated using Cox regression models adjusted for age, sex, height, weight, current smoking, systolic blood pressure, diastolic blood pressure, hypertension treatment, diabetes mellitus, valvular heart disease, prevalent myocardial infarction, and prevalent heart failure. We used the false discovery rate to account for multiple testing. RESULTS: The study sample comprised 3378 participants (54% women) with mean (SD) age of 61.5 (8.4) years. In total, 401 developed AF over a mean follow-up of 12.3±3.8 years. We observed lower hazard of incident AF associated with higher mean levels of IGF1 (insulin-like growth factor 1; hazard ratio per 1 SD increment in protein level, 0.84 [95% CI, 0.76-0.93]), and higher hazard of incident AF associated with higher mean levels of both IGFBP1 (insulin-like growth factor-binding protein 1; hazard ratio, 1.24 [95% CI, 1.1-1.39]) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; hazard ratio, 1.73 [95% CI, 1.52-1.96]). CONCLUSIONS: Decreased levels of IGF1 and increased levels of IGFBP1 and NT-proBNP were associated with higher risk of incident AF.

Inherited causes of clonal haematopoiesis in 97,691 whole genomes

Nature · 2020 · 726 citations

• Biology
• Genetics