DunedinPACE, a DNA methylation biomarker of the pace of aging

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al. 2020). Here we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome).Methods: We used data from the Dunedin Study 1972-3 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets.Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge.Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience.Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

So Where Do You See This Going? The Effects of Commitment Asymmetry and Asynchrony on Relationship Satisfaction and Breakup

We test the contribution of multiple types of romantic partners’ commitment asymmetry (discrepancies between partners’ commitment at a single time point) and asynchrony (discrepancies in the progression of commitment over time) to later relationship satisfaction and breakup. In three dyadic studies (N = 6,960 couples) over months (Study 1), days (Study 2), and years (Study 3), commitment asymmetry and asynchrony consistently did not predict satisfaction or breakup when controlling for commitment scores of individuals and their partners. Only one’s own commitment and proportion of downturns in commitment (when participants reported lower commitment than the previous time point) consistently predicted satisfaction across all three studies. For breakup, women’s (but not men’s) commitment was consistently negatively associated with breakup and proportion of downturns was consistently positively associated with breakup. Our findings indicate that, contrary to some significant findings in prior research, commitment asymmetry and asynchrony are not indicative of future relationship outcomes.

Pharmacy-Based Opportunistic Atrial Fibrillation Screening at a Community Level: A Real-Life Study

Purpose: Opportunistic pharmacy-based screening of atrial fibrillation (AF) appears effective, but the proportion of detected citizens is unknown. The aim of our real-life study was to determine rates of screening in a community population according to age group and gender. Methods: We conducted four community campaigns of pharmacy-based single-time point AF screening that involved individuals ≥65 years. We used a single-lead and hand-held device MyDiagnostick (6229 EV Maastricht, The Netherlands) that generates a 60-s ECG trace. All pharmacies of the communities (n = 54) were involved. Rates of screening were assessed on the base of the French National Institute for Statistics and Economic Studies data and were expressed as percentage and 95% Confidence interval (CI). Results: We screened 4208 individuals (Mean age, 74.2 ± 6.6 years; females, 60.2%). The screening rate in citizens aged ≥65 years was 17.2% (16.6–17.7), and higher in females than in males (17.9% [17.3–18.6] versus 16.0 [15.3–16.8], p < 0.001). The 70–74 age group showed the highest rate (25.7% [24.4–27]) compared to other groups. After 74 years, screening rates decreased steadily with age and dropped to 4.8% [3.8–6.1] in very elderly (≥90). Among the 188 (4.47%) positive screening, 117 (2.78%) showed an AF that was unknown in 53 (1.26%). Increasing age (OR: 1.05 [1.00–1.09], p = 0.04), male sex (OR: 4.30 [2.33–7.92], p < 0.0001) and high CHA2DS2-Vasc (OR: 1.59 [1.21–2.09], p = 0.0008) were independent predictors of unknown AF. Conclusion: Single-lead AF detection performed in community pharmacies result in screening one in six elderly citizens. Although male sex and elderly predicted unknown AF diagnosis, they were less involved in such designed campaigns.

Theoretical aspects on the use of single-time-point dosimetry for radionuclide therapy

Objective: This study considers the error distributions for time-integrated activity (TIA) of single-time-point (STP) methods for patient-specific dosimetry in radionuclide therapy. Approach: The general case with the same pharmaceutical labelled with different radionuclides for imaging and therapy are considered for a mono-exponential time-activity curve. Two methods for STP dosimetry, both based on the combination of one activity estimate with the population-mean effective decay constant, are investigated. The cumulative distribution functions (CDFs) and the probability density functions for the two methods are analytically derived for arbitrary distributions of the biological decay constant. The CDFs are used for determining 95 % coverage intervals of the relative errors for different combinations of imaging time points, physical decay constants, and relative standard deviations of the biological decay constant. Two examples, in the form of kidney dosimetry in [177Lu]Lu-DOTA-TATE therapy and tumour dosimetry for Na[131I]I therapy for thyroid cancer with dosimetry based on imaging of Na[124I]I, are also studied in more detail with analysis of the sensitivity with respect to errors in the mean biological decay constant and to higher moments of the distribution. Main results: The distributions of the relative errors are negatively skewed, potentially leading to the situation that some TIA estimates are highly underestimated even if the majority of estimates are close to the true value. Significance: The main limitation of the studied STP dosimetry methods is thereby the risk of large underestimations of the TIA.

Residential suburbanisation in the hinterland of Bratislava – a case study of municipalities in the Austrian border area

This paper provides an overview of the process of residential suburbanisation in the hinterland of Bratislava. The study focuses on the municipalities around the Austrian border area. The main aim of the paper is to investigate the characteristics of cross-border suburbanisation, which is a significant spatial phenomenon in the municipalities of northern Burgenland and the south-eastern part of Lower Austria. The analysis has a spatio-temporal dimension, as it depicts the time-space characteristics of the phenomenon – both for a single time point, as well as for a time series from the approximate beginning of the onset of suburbanisation up to the present. While monitoring the growth of the number of Slovaks in the study area, we observed a gradual increase in all the selected municipalities of the Austrian border area, with the distance from Bratislava being a significant factor here. The analysis of migration in the surveyed municipalities showed predominantly positive migration efficiency – immigration was negated by emigration only to a small extent (compared to suburbanisation in the Slovak hinterland of Bratislava, which is, however, relatively high). The structural characteristics of Slovak immigrants, where the younger age group of 30 to 44 years followed by a child component up to 14 years predominated, attest to the ongoing process of suburbanisation. The research confirmed the advancing residential suburbanisation and expansion of the cross-border suburban hinterland of Bratislava.

Trajectories of Depressive Symptoms and Incident Diabetes: A Prospective Study

Background Elevated depressive symptoms are associated with an increased risk for diabetes. Depression is a heterogeneous and chronic condition in which symptoms may remit, emerge, lessen, or intensify over time. Purpose The purpose of this study was to determine if trajectories of depressive symptoms measured at five time points over 8 years predicted incident diabetes over an 8-year follow-up in middle-aged and older adults. A secondary aim was to determine if trajectories of depressive symptoms predict incident diabetes, above and beyond depressive symptoms measured at a single time point. Methods Data came from the Health and Retirement Study (n = 9,233). Depressive symptoms were measured biennially from 1998 to 2006. Self-reported incident diabetes was measured during an 8-year follow-up. Results Five trajectories of depressive symptoms were identified (no depressive symptoms, low depressive symptoms, low-moderate depressive symptoms, moderate depressive symptoms, elevated and increasing depressive symptoms). Compared to the no depressive symptoms trajectory group (referent), all other trajectory groups were at higher risk of developing diabetes after adjusting for covariates. In most cases, trajectory group membership was associated with incident diabetes after controlling for depressive symptoms at a single time point. Conclusions Patterns of depressive symptoms over time were associated with incident diabetes. Patterns of depressive symptoms may be more predictive of diabetes incidence than depressive symptoms measured at a single time point.

Improved Detectability of Plasmodium falciparum Clones with Repeated Sampling in Incident and Chronic Infections in Burkina Faso

We evaluated the detectability of Plasmodium falciparum clones when assessed on 3 consecutive days in incident and chronic infections in naturally exposed children living in an area of intense malaria transmission in Burkina Faso. The median number of clones by merozoite surface protein 2 (MSP2) genotyping was 3 (interquartile range [IQR] 2–5) in incident infections compared with 6 (IQR 4–8) in chronic infections (P < 0.0001). When all clones detected on days 1-3 were considered as true complexity of infection, sampling on day 1 detected only 69.4% (109/157) or 68.3% (228/334) of all clones in incident and chronic infections, respectively. Our findings demonstrate that a large proportion of clones are missed by single time-point sampling. In addition, because of the high complexity of infection early in incident infections, our data suggest many infections may be caused by genetically complex inocula.

Trajectories of high-sensitivity cardiac troponin I in the two decades before cardiovascular death in Whitehall II

Background High-sensitivity cardiac troponin may be a promising biomarker that could be used for personalised cardiovascular risk prediction and monitoring in the general population. Temporal changes in high-sensitivity cardiac troponin before cardiovascular death are largely unexplored. Purpose Using the longitudinal Whitehall II cohort, we evaluated whether three serial high-sensitivity cardiac troponin I measurements over 15 years improved prediction of cardiovascular death when compared to a single time point at baseline. Methods Whitehall II is an ongoing longitudinal observation cohort study of 10,308 civil servants, and we included participants who had at least one cardiac troponin measurement and outcome data available. We constructed time trajectories to evaluate the temporal pattern of cardiac troponin I in those who died from cardiovascular disease as compared to those who did not. Cox regression and joint models were used to investigate the association of cardiac troponin I in relation to cardiovascular death using single time point (at baseline) and repeated measurements (at baseline, 10 and 15 years), respectively. The discriminative ability was assessed by the concordance index. Results In total, we included 7,293 individuals (mean age of 58 years [SD 7] at baseline, 29.4% women). Of these, 5,818 (79.8%) and 4,045 (55.5%) individuals had a second and third cardiac troponin I concentration measured, respectively. Cardiovascular death occurred in 281 (3.9%) individuals during a median follow-up of 21.4 [IQR, 15.8 to 21.8] years. In the 21-year trajectories of cardiac troponin I, we observed higher baseline concentrations in those who died due to cardiovascular disease as compared to those who did not (median 5 [IQR, 2 to 9] ng/L versus 3 [IQR, 2 to 5] ng/L respectively, Figure). Cardiac troponin I was an independent predictor of cardiovascular death, and the hazard ratio (HR) derived from the joint model that included serial cardiac troponin measurements was higher than the HR derived from the single time point model (single time point model: adjusted HR 1.53, 95% Confidence Interval [CI] 1.37 to 1.70 per naturally log transformed unit of cardiac troponin I, versus repeated measurements model: adjusted HR 1.79, 95% CI 1.58 to 2.02). The discriminative ability of the cardiac troponin model improved when using repeated measurements (concordance index of unadjusted cardiac troponin models, single time point: 0.668 versus repeated measurements: 0.724). Conclusions Our study shows that cardiac troponin I trajectories were persistently higher among individuals who died from cardiovascular disease. Cardiac troponin I is a strong independent predictor of cardiovascular death, and incorporating repeated measurements of cardiac troponin improves cardiovascular risk prediction in the general population. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Cardiac troponin I measurements and analysis were supported by were supported by Siemens Healthineers. The study was supported by Health Data Research UK which receives its funding from HDR UK Ltd (HDR-5012) funded by the UK Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council, Department of Health and Social Care (England), Chief Scientist Office of the Scottish Government Health and Social Care Directorates, Health and Social Care Research and Development Division (Welsh Government), Public Health Agency (Northern Ireland), British Heart Foundation and the Wellcome Trust. NLM is supported by the British Heart Foundation through a Senior Clinical Research Fellowship (FS/16/14/32023), Programme Grant (RG/20/10/34966) and a Research Excellence Award (RE/18/5/34216). The funders had no role in the study and the decision to submit this work to be considered for publication.