COX MODELS WITH NONLINEAR EFFECT OF COVARIATES MEASURED WITH ERROR: A CASE STUDY OF CHRONIC KIDNEY DISEASE INCIDENCE

We propose, develop and implement the simulation extrapolation (SIMEX) methodology for Cox regression models when the log hazard function is linear in the model parameters but nonlinear in the variables measured with error (LPNE). The class of LPNE functions contains but is not limited to strata indicators, splines, quadratic and interaction terms. The first order bias correction method proposed here has the advantage that it remains computationally feasible even when the number of observations is very large and multiple models need to be explored. Theoretical and simulation results show that the SIMEX method outperforms the naive method even with small amounts of measurement error. Our methodology was motivated by and applied to the study of time to chronic kidney disease (CKD) progression as a function of baseline kidney function and applied to the Atherosclerosis Risk in Communities (ARIC), a large epidemiological cohort stud

Short-Term Prognostic Impact of Arterial Stiffness in Older Adults Without Prevalent Cardiovascular Disease

Arterial stiffness, represented as carotid-femoral pulse wave velocity (cfPWV), predicts cardiovascular disease (CVD). In older populations, however, this association seems attenuated. Moreover, the prognostic values of pulse wave velocity at different arterial segments and newer parameters like cardio-ankle vascular index (CAVI) remain unclear, especially in US older adults. In 3034 Atherosclerosis Risk in Communities (ARIC) study participants (66-90 years) without CVD, we examined the associations of 4 pulse wave velocity measures (cfPWV, heart-femoral, brachial-ankle, heart-ankle) and 2 new measures of arterial stiffness (CAVI and cardio-femoral vascular index derived from heart-ankle and heart-femoral, respectively) with incident CVD (coronary disease, stroke, and heart failure) and all-cause mortality. Over a median follow-up of 4.4 years, there were 168 incident CVD events and 244 deaths. Overall, stiffness measures did not show strong associations with CVD, except cfPWV, which demonstrated a J-shaped association even after adjusting for potential confounders (hazard ratio, 1.83 [95% CI, 1.08-3.09] in top quartile and 1.97 [1.14-3.39] in bottom quartile versus second bottom quartile). When each CVD was examined separately, heart failure was most robustly associated with higher cfPWV, and stroke was strongly associated with lower cfPWV. There were no significant associations with all-cause mortality. Among different measures of pulse wave velocity, cfPWV showed the strongest associations with CVD, especially heart failure, in older adults without CVD. Other pulse wave velocity measures had no strong associations. Our findings further support cfPWV as the index measure of arterial stiffness and the link of arterial stiffness to heart failure development but also suggest somewhat limited prognostic value of arterial stiffness in older adults overall

Assessing Kidney Function — Measured and Estimated Glomerular Filtration Rate

Many organizations recommend the use of equations that estimate the glomerular filtration rate (GFR) to facilitate the detection, evaluation, and management of chronic kidney disease.1-11 Indeed, many clinical laboratories already report estimated GFR values whenever the serum creatinine level is measured. In this review, we discuss the strengths and weaknesses of current methods of measuring and estimating GFR as applied to chronic kidney disease

Carotid Intima-Media Thickness and Incident ESRD: The Atherosclerosis Risk in Communities (ARIC) Study

Carotid intima-media thickness has been reported to predict kidney function decline. However, whether carotid intima-media thickness is associated with a hard kidney end point, ESRD, has not been investigated

Comparing the association of GFR estimated by the CKD-EPI and MDRD study equations and mortality: the third national health and nutrition examination survey (NHANES III)

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration equation for estimation of glomerular filtration rate (eGFR(CKD-EPI)) improves GFR estimation compared with the Modification of Diet in Renal Disease Study equation (eGFR(MDRD)) but its association with mortality in a nationally representative population sample in the US has not been studied. METHODS: We examined the association between eGFR and mortality among 16,010 participants of the Third National Health and Nutrition Examination Survey (NHANES III). Primary predictors were eGFR(CKD-EPI) and eGFR(MDRD). Outcomes of interest were all-cause and cardiovascular disease (CVD) mortality. Improvement in risk categorization with eGFR(CKD-EPI) was evaluated using adjusted relative hazard (HR) and Net Reclassification Improvement (NRI). RESULTS: Overall, 26.9% of the population was reclassified to higher eGFR categories and 2.2% to lower eGFR categories by eGFR(CKD-EPI,) reducing the proportion of prevalent CKD classified as stage 3–5 from 45.6% to 28.8%(.) There were 3,620 deaths (1,540 from CVD) during 215,082 person-years of follow-up (median, 14.3 years). Among those with eGFR(MDRD) 30–59 ml/min/1.73 m(2), 19.4% were reclassified to eGFR(CKD-EPI) 60–89 ml/min/1.73 m(2) and these individuals had a lower risk of all-cause mortality (adjusted HR, 0.53; 95% CI, 0.34-0.84) and CVD mortality (adjusted HR, 0.51; 95% CI, 0.27-0.96) compared with those not reclassified. Among those with eGFR(MDRD) >60 ml/min/1.73 m(2), 0.5% were reclassified to lower eGFR(CKD-EPI) and these individuals had a higher risk of all-cause (adjusted HR, 1.31; 95% CI, 1.01-1.69) and CVD (adjusted HR, 1.42; 95% CI, 1.01-1.99) mortality compared with those not reclassified. Risk prediction improved with eGFR(CKD-EPI); NRI was 0.21 for all-cause mortality (p < 0.001) and 0.22 for CVD mortality (p < 0.001). CONCLUSIONS: eGFR(CKD-EPI) categories improve mortality risk stratification of individuals in the US population. If eGFR(CKD-EPI) replaces eGFR(MDRD) in the US, it will likely improve risk stratification

Lifetime Risk of Lower-Extremity Peripheral Artery Disease Defined by Ankle-Brachial Index in the United States.

Background There are no available lifetime risk estimates of lower-extremity peripheral artery disease (PAD). Methods and Results Using data from 6 US community-based cohorts and the vital statistics, we estimated the prevalence and incidence of PAD, defined as an ankle-brachial index&nbsp;&lt;&nbsp;0.90, at each year of age from birth to 80&nbsp;years for white, black, and Hispanic men and women. Then, we used Markov Monte Carlo simulations in a simulated cohort of 100&nbsp;000 individuals to estimate lifetime risk of PAD. On the basis of odds ratios of PAD for traditional atherosclerotic risk factors (eg, diabetes mellitus and smoking), we developed a calculator providing residual lifetime risk of PAD. In an 80-year horizon, lifetime risks of PAD were 30.0% in black men and 27.6% in black women, but ≈19% in white men and women and ≈22% in Hispanic men and women. From another perspective, 9% of blacks were estimated to develop PAD by 60&nbsp;years of age, while the same proportion was seen at ≈70&nbsp;years for whites and Hispanics. The residual lifetime risk within the same race/ethnicity varied by 3.5- to 5-fold according to risk factors (eg, residual lifetime risk in 45-year-old black men was 19.9% when current smoking, diabetes mellitus, and history of cardiovascular disease were absent versus 70.4% when all were present). Conclusions In the United States, ≈30% of blacks are estimated to develop PAD during their lifetime, whereas the corresponding estimate is ≈20% for whites and Hispanics. The residual lifetime risk within the same race/ethnicity substantially varies according to traditional risk factors

Lower Extremity Peripheral Artery Disease and Quality of Life Among Older Individuals in the Community

BACKGROUND: Evidence regarding the association of lower extremity peripheral arterial disease with quality of life (QOL) is mainly from selected clinical populations or relatively small clinical cohorts. Thus, we investigated this association in community-derived populations. METHODS AND RESULTS: Using data of 5115 participants aged 66 to 90 years from visit 5 (2011-2013) of the Atherosclerosis Risk in Communities Study, we quantified the associations of ankle-brachial index (ABI) with several QOL parameters, including 12-item Short-Form Health Survey (SF-12), after accounting for potential confounders using linear and logistic regression models. Peripheral arterial disease defined by an ABI <0.90 (n=402), was independently associated with a low SF-12 Physical Component Summary score (-3.26 [95% CI -5.60 to -0.92]), compared to the ABI reference 1.10 to 1.19 (n=1900) but not with the Mental Component Summary score (-0.07 [-2.21 to 2.06]). A low ABI was significantly associated with poorer status of all SF-12 physical domains (physical functioning, role-physical, bodily pain, and general health) but only vitality out of 4 mental domains. Similarly, low ABI values were more consistently associated with other physically related QOL parameters (leisure-time exercise/activity/walking) than mentally related parameters (significant depressive symptoms and hopeless feeling). Lower physical QOL was observed even in individuals with borderline low ABI (0.90 to 0.99; n=426). CONCLUSIONS: Low ABI (even borderline) was independently associated with poor QOL, especially for physical components, in community-dwelling older adults. QOL is a critical element for older adults, and thus, further studies are warranted to assess whether peripheral arterial disease-specific management can improve QOL in older populations

MMP2 genetic variation is associated with measures of fibrous cap thickness: The Atherosclerosis Risk in Communities Carotid MRI Study

Objective- Genetic variation in matrix metalloproteinase (MMP) promoter regions alters the transcriptional activity of MMPs and has been consistently associated with CHD, presumably through plaque degradation and remodeling. We examined the association of MMP promoter variation with multiple plaque characteristics measured by gadolinium-enhanced MRI among 1,700 participants in the Atherosclerosis Risk in Communities (ARIC) Carotid MRI Study. Methods—For the analyses presented here, 1,700 participants of the biracial ARIC Carotid MRI Study (~1,000 participants with thick carotid artery walls and ~700 randomly sampled participants) were evaluated for associations of MMP genetic variation with multiple plaque characteristics, including carotid artery wall thickness, lipid core and fibrous cap measures. MRI studies were performed on a 1.5T scanner equipped with a bilateral 4-element phased array carotid coil. Results—Fifty-one percent of the participants were female, 77% white, 23% African American, and the mean age was 70 years. MMP2 C-1306T variant genotypes (CT+TT) were significantly associated with higher cap thickness measures, but not with wall thickness or lipid core measures. Individuals with the CC genotype had approximately 0.1 mm thinner cap thickness compared to those carrying a T allele (p=0.02). Conclusion—Genetic variation within the MMP2 promoter region was associated with cap thickness and therefore may influence the role of MMP2 in plaque vulnerability