16 research outputs found
Development of Risk Prediction Equations for Incident Chronic Kidney Disease
IMPORTANCE ‐ Early identification of individuals at elevated risk of developing chronic kidney disease
could improve clinical care through enhanced surveillance and better management of underlying health
conditions.
OBJECTIVE – To develop assessment tools to identify individuals at increased risk of chronic kidney
disease, defined by reduced estimated glomerular filtration rate (eGFR).
DESIGN, SETTING, AND PARTICIPANTS – Individual level data analysis of 34 multinational cohorts from
the CKD Prognosis Consortium including 5,222,711 individuals from 28 countries. Data were collected from April, 1970 through January, 2017. A two‐stage analysis was performed, with each study first
analyzed individually and summarized overall using a weighted average. Since clinical variables were often differentially available by diabetes status, models were developed separately within participants
with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external
cohorts (N=2,253,540).
EXPOSURE Demographic and clinical factors.
MAIN OUTCOMES AND MEASURES – Incident eGFR <60 ml/min/1.73 m2.
RESULTS – In 4,441,084 participants without diabetes (mean age, 54 years, 38% female), there were
660,856 incident cases of reduced eGFR during a mean follow‐up of 4.2 years. In 781,627 participants
with diabetes (mean age, 62 years, 13% female), there were 313,646 incident cases during a mean
follow‐up of 3.9 years. Equations for the 5‐year risk of reduced eGFR included age, sex, ethnicity, eGFR,
history of cardiovascular disease, ever smoker, hypertension, BMI, and albuminuria. For participants
with diabetes, the models also included diabetes medications, hemoglobin A1c, and the interaction
between the two. The risk equations had a median C statistic for the 5‐year predicted probability of
0.845 (25th – 75th percentile, 0.789‐0.890) in the cohorts without diabetes and 0.801 (25th – 75th
percentile, 0.750‐0.819) in the cohorts with diabetes. Calibration analysis showed that 9 out of 13 (69%)
study populations had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was
similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 out of 18
(89%) had a slope of observed to predicted risk between 0.80 and 1.25.
CONCLUSIONS AND RELEVANCE – Equations for predicting risk of incident chronic kidney disease
developed in over 5 million people from 34 multinational cohorts demonstrated high discrimination and
variable calibration in diverse populations
Relation of multi-marker panel to incident chronic kidney disease and rapid kidney function decline in African Americans: the Jackson Heart Study
Abstract Background Few investigations have evaluated the incremental usefulness of multiple biomarkers representing varying physiological pathways for predicting risk of renal outcomes in African Americans. Design, setting, participants, and measurements We related a multi-marker panel to incident chronic kidney disease (CKD) and rapid kidney function decline (RKFD) in 2813 Jackson Heart Study participants without prevalent CKD at exam 1 (2000–2004) and with complete assays at exam 1 for 9 biomarkers: adiponectin, aldosterone, B-natriuretic peptide [BNP], cortisol, high sensitivity C-reactive protein (hsCRP), endothelin, homocysteine, plasma renin activity and mass. Incident CKD was defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 at exam 3 while RKFD was defined as eGFR ≥30% loss between exams 1 and 3 (8.2 median years). We employed multiple logistic regression model to describe association between the panel and incident CKD and RKFD and used backward elimination strategy to estimate the most parsimonious biomarker model while controlling for conventional risk factors. Results The multi-marker panel predicted the risk for both incident CKD (odds ratios [OR], 2.72; 95% confidence intervals [CI], 1.63, 4.56; P = 0.001) and RKFD (2.61; 95% CI, 1.67, 4.08; P < 0.001). Per standard deviation increase in log biomarker concentrations were significantly (multivariable adjusted odds ratios, [95% confidence interval], p-value) associated with incident CKD: plasma adiponectin (1.24 [1.07, 1.44], p = 0.005) and leptin (1.3 [1.06, 1.61], p = 0.011), and with RKFD: plasma adiponectin (1.22 [1.06, 1.40], p = 0.006); hsCRP (1.17 [1.01, 1.36], p = 0.031) and aldosterone (0.85 [0.74, 0.96], p = 0.012). Moderate levels (3rd quartile) of aldosterone were inversely associated with incident CKD (0.54 [0.35, 0.82], p = 0.004) while leptin was associated with RKFD (1.64 [1.10, 2.44], p = 0.015). Biomarkers improved CKD risk prediction (P = 0.003) but not RKFD risk prediction (P = 0.10). Conclusion In this community-based sample of African Americans, a multi-marker panel added only moderate predictive improvement compared to conventional risk factors
Subclinical Atherosclerosis, Statin Eligibility, and Outcomes in African American Individuals: The Jackson Heart Study
Importance: Modern prevention guidelines substantially increase the number of individuals who are eligible for treatment with statins. Efforts to refine statin eligibility via coronary calcification have been studied in white populations but not, to our knowledge, in large African American populations.
Objective: To compare the relative accuracy of US Preventive Services Task Force (USPSTF) and American College of Cardiology/American Heart Association (ACC/AHA) recommendations in identifying African American individuals with subclinical and clinical atherosclerotic cardiovascular disease (ASCVD).
Design, Setting, and Participants: In this prospective, community-based study, 2812 African American individuals aged 40 to 75 years without prevalent ASCVD underwent assessment of ASCVD risk. Of these, 1743 participants completed computed tomography.
Main Outcomes and Measures: Nonzero coronary artery calcium (CAC) score, abdominal aortic calcium score, and incident ASCVD (ie, myocardial infarction, ischemic stroke, or fatal coronary heart disease).
Results: Of the 2812 included participants, the mean (SD) age at baseline was 55.4 (9.4) years, and 1837 (65.3%) were female. The USPSTF guidelines captured 404 of 732 African American individuals (55.2%) with a CAC score greater than 0; the ACC/AHA guidelines identified 507 individuals (69.3%) (risk difference, 14.1%; 95% CI, 11.2-17.0; P \u3c .001). Statin recommendation under both guidelines was associated with a CAC score greater than 0 (odds ratio, 5.1; 95% CI, 4.1-6.3; P \u3c .001). While individuals indicated for statins under both guidelines experienced 9.6 cardiovascular events per 1000 patient-years, those indicated under only ACC/AHA guidelines were at low to intermediate risk (4.1 events per 1000 patient-years). Among individuals who were statin eligible by ACC/AHA guidelines, the 10-year ASCVD incidence per 1000 person-years was 8.1 (95% CI, 5.9-11.1) in the presence of CAC and 3.1 (95% CI, 1.6-5.9) without CAC (P = .02). While statin-eligible individuals by USPSTF guidelines did not have a significantly higher 10-year ASCVD event rate in the presence of CAC, African American individuals not eligible for statins by USPSTF guidelines had a higher ASCVD event rate in the presence of CAC (2.8 per 1000 person-years; 95% CI, 1.5-5.4) relative to without CAC (0.8 per 1000 person-years; 95%, CI 0.3-1.7) (P = .03).
Conclusions and Relevance: The USPSTF guidelines focus treatment recommendations on 38% of high-risk African American individuals at the expense of not recommending treatment in nearly 25% of African American individuals eligible for statins by ACC/AHA guidelines with vascular calcification and at low to intermediate ASCVD risk
Ideal Cardiovascular Health, Cardiovascular Remodeling, and Heart Failure in Blacks: The Jackson Heart Study.
BACKGROUND: The lifetime risk of heart failure is higher in the African-American population than in other racial groups in the United States. METHODS AND RESULTS: We measured the Life’s Simple 7 ideal cardiovascular health metrics in 4195 African-Americans in the Jackson Heart Study (2000–2004). We evaluated the association of Simple 7 metrics with incident HF and left ventricular (LV) structure and function by cardiac magnetic resonance (CMR; n=1188). Mean age at baseline was 54.4 years (65% women). Relative to 0–2 Simple 7 factors, African-Americans with 3 factors had 47% lower incident HF risk (HR 0.53, 95% CI 0.39–0.73, P<0.0001); those with ≥ 4 factors had 61% lower HF risk (HR 0.39, 95% CI 0.24–0.64, P=0.0002). Higher blood pressure (HR 2.32, 95% CI 1.28–4.20, P=0.005), physical inactivity (HR 1.65, 95% CI 1.07–2.55, P=0.02), smoking (HR 2.04, 95% CI 1.43–2.91, P<0.0001) and impaired glucose control (HR 1.76, 95% CI 1.34–2.29, P<0.0001) were associated with incident HF. The age-/sex-adjusted population attributable risk for these Simple 7 metrics combined was 37.1%. Achievement of ideal blood pressure, ideal body mass index, ideal glucose control, and non-smoking was associated with less likelihood of adverse cardiac remodeling by CMR. CONCLUSIONS: Cardiovascular risk factors in mid-life (specifically elevated blood pressure, physical inactivity, smoking and poor glucose control) are associated with incident HF in African Americans, and represent targets for intensified HF prevention
Gene-by-Psychosocial Factor Interactions Influence Diastolic Blood Pressure in European and African Ancestry Populations: Meta-Analysis of Four Cohort Studies
Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors
Rare coding variants in RCN3 are associated with blood pressure
BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries. RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N = 403,522), and reached genome-wide significance for diastolic blood pressure (p = 2.01 × 10). CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits
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Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.
In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data