Quantile-specific heritability of plasma fibrinogen concentrations

Background Fibrinogen is a moderately heritable blood protein showing different genetic effects by sex, race, smoking status, pollution exposure, and disease status. These interactions may be explained in part by “quantile-dependent expressivity”, where the effect size of a genetic variant depends upon whether the phenotype (e.g. plasma fibrinogen concentration) is high or low relative to its distribution. Purpose Determine whether fibrinogen heritability (h2) is quantile-specific, and whether quantile-specific h2 could account for fibrinogen gene-environment interactions. Methods Plasma fibrinogen concentrations from 5689 offspring-parent pairs and 1932 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (βOP, h2 = 2βOP/(1+rspouse)) and full-sib regression slopes (βFS, h2 = {(1+8rspouseβFS)0.05–1}/(2rspouse)) were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results Quantile-specific h2 (±SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted fibrinogen distribution when estimated from βOP (Ptrend = 5.5x10-6): 0.30±0.05 at the 10th, 0.37±0.04 at the 25th, 0.48±0.05 at the 50th, 0.61±0.06 at the 75th, and 0.65±0.08 at the 90th percentile, and when estimated from βFS (Ptrend = 0.008): 0.28±0.04 at the 10th, 0.31±0.04 at the 25th, 0.36±0.03 at the 50th, 0.41±0.05 at the 75th, and 0.50±0.06 at the 90th percentile. The larger genetic effect at higher average fibrinogen concentrations may contribute to fibrinogen’s greater heritability in women than men and in Blacks than Whites, and greater increase from smoking and air pollution for the FGB -455G>A A-allele. It may also explain greater fibrinogen differences between: 1) FGB -455G>A genotypes during acute phase reactions than usual conditions, 2) GTSM1 and IL-6 -572C>G genotypes in smokers than nonsmokers, 3) FGB -148C>T genotypes in untreated than treated diabetics, and LPL PvuII genotypes in macroalbuminuric than normoalbuminuric patients. Conclusion Fibrinogen heritability is quantile specific, which may explain or contribute to its gene-environment interactions. The analyses do not disprove the traditional gene-environment interpretations of these examples, rather quantile-dependent expressivity provides an alternative explanation that warrants consideration.

Quantile-Dependent Heritability of Glucose, Insulin, Proinsulin, Insulin Resistance, and Glycated Hemoglobin

<b><i>Background:</i></b> “Quantile-dependent expressivity” is a dependence of genetic effects on whether the phenotype (e.g., insulin resistance) is high or low relative to its distribution. <b><i>Methods:</i></b> Quantile-specific offspring-parent regression slopes (β_OP) were estimated by quantile regression for fasting glucose concentrations in 6,453 offspring-parent pairs from the Framingham Heart Study. <b><i>Results:</i></b> Quantile-specific heritability (<i>h</i>²), estimated by 2β_OP/(1 + <i>r</i>_spouse), increased 0.0045 ± 0.0007 (<i>p</i> = 8.8 × 10⁻¹⁴) for each 1% increment in the fasting glucose distribution, that is, <i>h</i>² ± SE were 0.057 ± 0.021, 0.095 ± 0.024, 0.146 ± 0.019, 0.293 ± 0.038, and 0.456 ± 0.061 at the 10th, 25th, 50th, 75th, and 90th percentiles of the fasting glucose distribution, respectively. Significant increases in quantile-specific heritability were also suggested for fasting insulin (<i>p</i> = 1.2 × 10⁻⁶), homeostatic model assessment of insulin resistance (HOMA-IR, <i>p</i> = 5.3 × 10⁻⁵), insulin/glucose ratio (<i>p</i> = 3.9 × 10⁻⁵), proinsulin (<i>p</i> = 1.4 × 10⁻⁶), proinsulin/insulin ratio (<i>p</i> = 2.7 × 10⁻⁵), and glucose concentrations during a glucose tolerance test (<i>p</i> = 0.001), and their logarithmically transformed values. <b><i>Discussion/Conclusion:</i></b> These findings suggest alternative interpretations to precision medicine and gene-environment interactions, including alternative interpretation of reported synergisms between <i>ACE, ADRB3</i>, <i>PPAR-γ2</i>, and <i>TNF-α</i> polymorphisms and being born small for gestational age on adult insulin resistance (fetal origin theory), and gene-adiposity (<i>APOE, ENPP1, GCKR, IGF2BP2, IL-6, IRS-1, KIAA0280, LEPR, MFHAS1, RETN, TCF7L2</i>), gene-exercise (<i>INS</i>), gene-diet (<i>ACSL1</i>, <i>ELOVL6</i>, <i>IRS-1</i>, <i>PLIN</i>, <i>S100A9</i>), and gene-socioeconomic interactions.

Revisiting the Relationships between Fat-to-Protein Ratio in Milk and Energy Balance in Dairy Cows of Different Parities, and at Different Stages of Lactation

A statistical re-assessment of aggregated individual cow data was conducted to examine trends in fat-to-protein ratio in milk (FPR), and relationships between FPR and energy balance (EB, MJ of ME/day) in Holstein-Friesian dairy cows of different parities, and at different stages of lactation. The data were collected from 27 long-term production trials conducted between 1996 and 2016 at the Agri-Food and Biosciences Institute (AFBI) in Hillsborough, Northern Ireland. In total, 1321 lactations (1 to 20 weeks in milk; WIM), derived from 840 individual cows fed mainly grass silage-based diets, were included in the analysis. The energy balance was calculated daily and then averaged weekly for statistical analyses. Data were further split in 4 wk. intervals, namely, 1–4, 5–8, 9–12, 13–16, and 17–20 WIM, and both partial correlations and linear regressions (mixed models) established between the mean FPR and EB during these periods. Three FPR score categories (‘Low’ FPR, <1.0; ‘Normal’ FPR, 1.0–1.5; ‘High’ FPR, >1.5) were adopted and the performance and EB indicators within each category were compared. As expected, multiparous cows experienced a greater negative EB compared to primiparous cows, due to their higher milk production relative to DMI. Relatively minor differences in milk fat and protein content resulted in large differences in FPR curves. Second lactation cows displayed the lowest weekly FPR, and this trend was aligned with smaller BW losses and lower concentrations of non-esterified fatty acids (NEFA) until at least 8 WIM. Partial correlations between FPR and EB were negative, and ‘greatest’ in early lactation (1–4 WIM; r = −0.38 on average), and gradually decreased as lactation progressed across all parities (17–20 WIM; r = −0.14 on average). With increasing parity, daily EB values tended to become more negative per unit of FPR. In primiparous cows, regression slopes between FPR and EB differed between 1–4 and 5–8 WIM (−54.6 vs. −47.5 MJ of ME/day), while differences in second lactation cows tended towards significance (−57.2 vs. −64.4 MJ of ME/day). Irrespective of the lactation number, after 9–12 WIM, there was a consistent trend for the slope of the linear relationships between FPR and EB to decrease as lactation progressed, with this likely reflecting the decreasing milk nutrient demands of the growing calf. The incidence of ‘High’ FPR scores was greatest during 1–4 WIM, and decreased as lactation progressed. ‘High’ FPR scores were associated with increased energy-corrected milk (ECM) yields across all parities and stages of lactation, and with smaller BW gains and increasing concentrations (log transformed) of blood metabolites (non-esterified fatty acid, NEFA; beta-hydroxybutyrate, BHB) until 8 WIM. Results from the present study highlight the strong relationships between FPR in milk, physiological changes, and EB profiles during early lactation. However, while FPR can provide an indication of EB at a herd level, the large cow-to-cow variation indicates that FPR cannot be used as a robust indicator of EB at an individual cow level.

The relationship between PM2.5 and anti-cyclone wave activity during summer over the United States

To better understand the role of atmospheric dynamics in modulating surface concentrations of fine particulate matter (PM2.5), we relate the anti-cyclone wave activity (AWA) metric and PM2.5 data from the Interagency Monitoring of Protected Visual Environment (IMPROVE) data for the period of 1988–2014 over the US. The observational results are compared with hindcast simulations over the past two decades using the National Center for Atmospheric Research-Community Earth System Model (NCAR CESM). We find that PM2.5 is positively correlated (up to R = 0.65) with AWA changes close to the observing sites using regression analysis. The composite AWA for high aerosol days (all daily PM2.5 above the 90th percentile) shows a similarly strong correlation between PM2.5 and AWA. The most prominent correlation occurs in the Midwestern US. Furthermore, the higher quantiles of PM2.5 levels are more sensitive to the changes in AWA. For example, we find the averaged sensitivity of the 90th percentile PM2.5 to changes in AWA is approximately three times as strong as the sensitivity of 10th percentile PM2.5 at one site (Arendtsville, Pennsylvania; 39.92° N, 77.31° W). The higher values of the 90th percentile compared to the 50th percentile in quantile regression slopes are most prominent over the northeastern US. In addition, future changes in US PM2.5 based only on changes in climate are estimated to increase PM2.5 concentrations due to increased AWA in summer over areas where PM2.5 variations are dominated by meteorological changes, especially over the western US. Changes between current and future climates in AWA can explain up to 75 % of PM2.5 variability using a linear regression model. Our analysis indicates that higher PM2.5 concentrations occur when a positive AWA anomaly is prominent, which could be critical for understanding how pollutants respond to changing atmospheric circulation, as well as developing robust pollution projections.

Quantile-Dependent Expressivity of Serum Uric Acid Concentrations

Objective. “Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., serum uric acid) is high or low relative to its distribution. Analyses were performed to test whether serum uric acid heritability is quantile-specific and whether this could explain some reported gene-environment interactions. Methods. Serum uric acid concentrations were analyzed from 2151 sibships and 12,068 offspring-parent pairs from the Framingham Heart Study. Quantile-specific heritability from offspring-parent regression slopes ( β OP , h 2 = 2 β OP / 1 + r spouse ) and full-sib regression slopes ( β FS , h 2 = 1 + 8 r spouse β FS 0.5 − 1 / 2 r spouse ) was robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. Results. Quantile-specific h 2 (±SE) increased with increasing percentiles of the offspring’s sex- and age-adjusted uric acid distribution when estimated from β OP P trend = 0.001 : 0.34 ± 0.03 at the 10th, 0.36 ± 0.03 at the 25th, 0.41 ± 0.03 at the 50th, 0.46 ± 0.04 at the 75th, and 0.49 ± 0.05 at the 90th percentile and when estimated from β FS P trend = 0.006 . This is consistent with the larger genetic effect size of (1) the SLC2A9 rs11722228 polymorphism in gout patients vs. controls, (2) the ABCG2 rs2231142 polymorphism in men vs. women, (3) the SLC2A9 rs13113918 polymorphism in obese patients prior to bariatric surgery vs. two-year postsurgery following 29 kg weight loss, (4) the ABCG2 rs6855911 polymorphism in obese vs. nonobese women, and (5) the LRP2 rs2544390 polymorphism in heavier drinkers vs. abstainers. Quantile-dependent expressivity may also explain the larger genetic effect size of an SLC2A9/PKD2/ABCG2 haplotype for high vs. low intakes of alcohol, chicken, or processed meats. Conclusions. Heritability of serum uric acid concentrations is quantile-specific.

Comparison of Four-Dimensional Flow Magnetic Resonance Imaging and Particle Image Velocimetry to Quantify Velocity and Turbulence Parameters

Although recent advances of four-dimensional (4D) flow magnetic resonance imaging (MRI) has introduced a new way to measure Reynolds stress tensor (RST) in turbulent flows, its measurement accuracy and possible bias have remained to be revealed. The purpose of this study was to compare the turbulent flow measurement of 4D flow MRI and particle image velocimetry (PIV) in terms of velocity and turbulence quantification. Two difference flow rates of 10 and 20 L/min through a 50% stenosis were measured with both PIV and 4D flow MRI. Not only velocity through the stenosis but also the turbulence parameters such as turbulence kinetic energy and turbulence production were quantitatively compared. Results shows that 4D flow MRI velocity measurement well agreed with the that of PIV, showing the linear regression slopes of two methods are 0.94 and 0.89, respectively. Although turbulence mapping of 4D flow MRI was qualitatively agreed with that of PIV, the quantitative comparison shows that the 4D flow MRI overestimates RST showing the linear regression slopes of 1.44 and 1.66, respectively. In this study, we demonstrate that the 4D flow MRI visualize and quantify not only flow velocity and also turbulence tensor. However, further optimization of 4D flow MRI for better accuracy might be remained.

Variation in Ontogenetic Facial Suture Fusion Patterns in Catarrhines

Timing of craniofacial suture fusion is important for the determination of demographics and primate ontogeny. There has been much work concerning the timing of fusion of calvarial sutures over the last century, but little comprehensive work focusing on facial sutures. Here we assess the relationships of facial suture fusion across ontogeny among select catarrhines. Fusion timing patterns for 5 facial sutures were examined in 1,599 crania of <i>Homo</i>, <i>Pan</i>, <i>Gorilla</i>, <i>Pongo</i>, Hylobatidae, <i>Papio</i>, and <i>Macaca</i>. Calvarial volume (early ontogeny) and dental eruption (late ontogeny) were used as indicators of stage of development. General linear models, test for homogeneity of slopes, and ANOVA were used to determine differences in timing of fusion by taxon. For calvarial volume, taxonomic groups segregated by regression slopes, with models for <i>Homo</i> indicating sutural fusion throughout ontogeny, <i>Pongo</i>, <i>Macaca</i>, and <i>Papio</i> representing earlier and more complete suture fusion, and <i>Pan</i>, <i>Gorilla</i>, and Hylobatidae indicating very early facial suture fusion. Similar patterns are observed when dental eruption is used for developmental staging. Only <i>Gorilla</i> and Hylobatidae are observed to, generally, fuse all facial suture sites in adulthood. Finally, <i>Homo</i> appears to be unique in its delay and patency of sutures into late ontogeny. The taxonomic patterns of facial suture closure identified in this study likely reflect important evolutionary shifts in facial growth and development in catarrhines.

Respiration Monitoring via Forcecardiography Sensors

In the last few decades, a number of wearable systems for respiration monitoring that help to significantly reduce patients’ discomfort and improve the reliability of measurements have been presented. A recent research trend in biosignal acquisition is focusing on the development of monolithic sensors for monitoring multiple vital signs, which could improve the simultaneous recording of different physiological data. This study presents a performance analysis of respiration monitoring performed via forcecardiography (FCG) sensors, as compared to ECG-derived respiration (EDR) and electroresistive respiration band (ERB), which was assumed as the reference. FCG is a novel technique that records the cardiac-induced vibrations of the chest wall via specific force sensors, which provide seismocardiogram-like information, along with a novel component that seems to be related to the ventricular volume variations. Simultaneous acquisitions were obtained from seven healthy subjects at rest, during both quiet breathing and forced respiration at higher and lower rates. The raw FCG sensor signals featured a large, low-frequency, respiratory component (R-FCG), in addition to the common FCG signal. Statistical analyses of R-FCG, EDR and ERB signals showed that FCG sensors ensure a more sensitive and precise detection of respiratory acts than EDR (sensitivity: 100% vs. 95.8%, positive predictive value: 98.9% vs. 92.5%), as well as a superior accuracy and precision in interbreath interval measurement (linear regression slopes and intercepts: 0.99, 0.026 s (R2 = 0.98) vs. 0.98, 0.11 s (R2 = 0.88), Bland–Altman limits of agreement: ±0.61 s vs. ±1.5 s). This study represents a first proof of concept for the simultaneous recording of respiration signals and forcecardiograms with a single, local, small, unobtrusive, cheap sensor. This would extend the scope of FCG to monitoring multiple vital signs, as well as to the analysis of cardiorespiratory interactions, also paving the way for the continuous, long-term monitoring of patients with heart and pulmonary diseases.

Ocular foreign bodies: evolution of professional roles and public costs in Quebec

Purpose In 2003, Quebec optometrists were legally enabled to extract superficial ocular foreign bodies, with part of this service covered by the universal health insurance. This study analyses the evolution of roles for professionals managing this condition (optometrists, ophthalmologists, emergency physicians and family physicians) and the related public healthcare costs. Methods Data from the provincial health insurance were combined to demographic and annual healthcare workforce statistics. Across professions and sociosanitary regions, variations in annual rates of conditions treated were calculated, as well as variations in public healthcare costs. Linear regression slopes of these variations were used as indicators of linear trends. Results Between 2010 and 2016, the proportion of cases managed by optometrists increases from 32% to 44%, following a significant trend (p < 0.007). For family physicians, the proportion of cases managed decreases from 49% to 33%, following a significant trend (p < 0.0001). The increase in optometrists managing cases is visible in almost all sociosanitary regions, reaching +19%. A significant trend was observed for increasing healthcare costs for optometrists (p < 0.008) and ophthalmologists (p < 0.004) and for decreasing healthcare costs for family physicians (p < 0.001). In 2016, optometrists managed 44% of cases, representing 13% of related healthcare costs. Conclusion In Quebec, optometrists are now the professionals managing the largest proportion of superficial ocular foreign bodies, across the province. There is an apparent shift from the proportion of cases managed by family physicians, which have similarly decreased.

Underestimation of self-tilt increases in reduced gravity conditions

BACKGROUND: During large angles of self-tilt in the roll plane on Earth, measurements of the subjective visual vertical (SVV) in the dark show a bias towards the longitudinal body axis, reflecting a systematic underestimation of self-tilt. OBJECTIVE: This study tested the hypothesis that self-tilt is underestimated in partial gravity conditions, and more so at lower gravity levels. METHODS: The SVV was measured in parabolic flight at three partial gravity levels: 0.25, 0.50, and 0.75 g. Self-tilt was varied amongst 0, 15, 30, and 45 deg, using a tiltable seat. The participants indicated their SVV by setting a linear array of dots projected inside a head mounted display to the perceived vertical. The angles of participants’ body and head roll tilt relative to the gravito-inertial vertical were measured by two separate inertial measurement units. RESULTS: Data on six participants were collected. Per G-level, a regression analysis was performed with SVV setting as dependent variable and head tilt as independent variable. The latter was used instead of chair tilt, because not all the participants’ heads were aligned with their bodies. The estimated regression slopes significantly decreased with smaller G-levels, reflecting an increased bias of the SVV towards the longitudinal body axis. On average, the regression slopes were 0.95 (±0.38) at 0.75 g; 0.84 (±0.22) at 0.5 g; and 0.63 (±0.33) at 0.25 g. CONCLUSIONS: The results of this study show that reduced gravity conditions lead to increased underestimation of roll self-tilt.