Randomly selected profiles of test set subjects having low (< 2^nd percentile), median (49^th to 51^st percentiles) and high (> 98^th percentile) functional risk scores.

Randomly selected profiles of test set subjects having low (nd percentile), median (49th to 51st percentiles) and high (> 98th percentile) functional risk scores.</p

Subject characteristics in train and test set.

Subject characteristics in train and test set.</p

Cox model results of time to CVD event among test set subjects.

Cox model results of time to CVD event among test set subjects.</p

Example profile.

Solid line represents particle mass for a representative sample lipoprotein profile. Sizes: (VS = very small; S = small; M = Medium; L = Large). Regions: HDL = High Density Lipoprotein; MZ = Midzone; LDL = Low Density Lipoprotein; IDL = Intermediate Density Lipoprotein; VLDL = Very Low Density Lipoprotein.</p

Estimated Cox regression coefficients across ion mobility profile.

Solid line represents estimated regression coefficients. Dashed lines represent upper and lower 95% confidence intervals for regression coefficients. Points indicate regions of significance (95% CI does not include zero). Sizes: (VS = very small; S = small; M = Medium; L = Large) Regions: HDL = High Density Lipoprotein; MZ = Midzone; LDL = Low Density Lipoprotein; IDL = Intermediate Density Lipoprotein; VLDL = Very Low Density Lipoprotein.</p

Simulated coefficient profiles under an alternative hypothesis for nested spline series with 8 and 15 degrees of freedom.

N = 500 (Panel A) and N = 5000 (Panel B). Thick (black) line is true profile. Thin (colored) lines are representative simulated profiles.</p

Simulated coefficient profiles under an alternative hypothesis for nested spline series with 7 and 13 degrees of freedom.

N = 500 (Panel A) and N = 5000 (Panel B). Thick (black) line is true profile. Thin (colored) lines are representative simulated profiles.</p

Simulation results.

Simulation results.</p

Whiskers denote 95% confidence intervals derived from linear mixed models adjusted for age, sex, and principal components of genetic variation.

<p>Whiskers denote 95% confidence intervals derived from linear mixed models adjusted for age, sex, and principal components of genetic variation.</p

A Gene Variant in CERS2 Is Associated with Rate of Increase in Albuminuria in Patients with Diabetes from ONTARGET and TRANSCEND

<div><p>Although albuminuria and subsequent advanced stage chronic kidney disease are common among patients with diabetes, the rate of increase in albuminuria varies among patients. Since genetic variants associated with estimated glomerular filtration rate (eGFR) were identified in cross sectional studies, we asked whether these variants were also associated with rate of increase in albuminuria among patients with diabetes from ONTARGET and TRANSCEND—randomized controlled trials of ramipril, telmisartan, both, or placebo. For 16 genetic variants associated with eGFR at a genome-wide level, we evaluated the association with annual rate of increase in albuminuria estimated from urine albumin:creatinine ratio (uACR). One of the variants (rs267734) was associated with rate of increase in albuminuria. The annual rate of increase in albuminuria among risk homozygotes (69% of the study population) was 11.3% (95%CI; 7.5% to 15.3%), compared with 5.0% (95%CI; 3.3% to 6.8%) for heterozygotes (27% of the population), and 1.7% (95%CI; −1.7% to 5.3%) for non-risk homozygotes (4% of the population); P = 0.0015 for the difference between annual rates in the three genotype groups. These estimates were adjusted for age, sex, ethnicity, and principal component of genetic heterogeneity. Among patients without albuminuria at baseline (uACR<30 mg/g), each risk allele was associated with 50% increased risk of incident albuminuria (OR = 1.50; 95%CI 1.15 to 1.95; P = 0.003) after further adjustment for traditional risk factors including baseline uACR and eGFR. The rs267734 variant is in almost perfect linkage-disequilibrium (r² = 0.94) with rs267738, a single nucleotide polymorphism encoding a glutamic acid to alanine change at position 115 of the ceramide synthase 2 (CERS2) encoded protein. However, it is unknown whether CERS2 function influences albuminuria. In conclusion, we found that rs267734 in CERS2 is associated with rate of increase in albuminuria among patients with diabetes and elevated risk of cardiovascular disease.</p></div