Pathway-specific population attributable fractions.

INTRODUCTION: A population attributable fraction represents the relative change in disease prevalence that one might expect if a particular exposure was absent from the population. Often, one might be interested in what percentage of this effect acts through particular pathways. For instance, the effect of a sedentary lifestyle on stroke risk may be mediated by blood pressure, body mass index and several other intermediate risk factors. METHODS: We define a new metric, the pathway-specific population attributable fraction (PS-PAF), for mediating pathways of interest. PS-PAFs can be informally defined as the relative change in disease prevalence from an intervention that shifts the distribution of the mediator to its expected distribution if the risk factor were eliminated, and sometimes more simply as the relative change in disease prevalence if the mediating pathway were disabled. A potential outcomes framework is used for formal definitions and associated estimands are derived via relevant identifiability conditions. Computationally efficient estimators for PS-PAFs are derived based on these identifiability conditions. RESULTS: Calculations are demonstrated using INTERSTROKE-an international case-control study designed to quantify disease burden attributable to a number of known causal risk factors. The applied results suggest that mediating pathways from physical activity through blood pressure, blood lipids and body size explain comparable proportions of stroke disease burden, but a large proportion of the disease burden due to physical inactivity may be explained by alternative pathways. CONCLUSION: PS-PAFs measure disease burden attributable to differing mediating pathways and can generate insights into the dominant mechanisms by which a risk factor affects disease at a population level.

Multiplex Serum Biomarker Assays Improve Prediction of Renal and Mortality Outcomes in Chronic Kidney Disease.

BACKGROUND: We investigated the predictive value of 11 serum biomarkers for renal and mortality end points in people with CKD. METHODS: Adults with CKD (n=139) were enrolled from outpatient clinics between February 2014 and November 2016. Biomarker quantification was performed using two multiplex arrays on a clinical-grade analyzer. Relationships between biomarkers and renal and mortality end points were investigated by random forests and Cox proportional hazards regression. RESULTS: The cohort was 56% male. The mean age was 63 years and median (IQR) CKD-EPI eGFR was 33 (24-51) ml/min per BSA. A total of 56 (40%) people developed a composite end point defined as ≥40% decline in eGFR, doubling of serum creatinine, RRT, or death over median (IQR) follow-up of 5.4 (4.7-5.7) years. Prediction of the composite end point was better with random forests trained on serum biomarkers compared with clinical variables (area under the curve of 0.81 versus 0.78). The predictive performance of biomarkers was further enhanced when considered alongside clinical variables (area under the curve of 0.83 versus 0.81 for biomarkers alone). Patients (n=27, 19%) with high soluble TNF receptor-1 (≥3 ng/ml) and neutrophil gelatinase-associated lipocalin (≥156 ng/ml), coupled with low complement 3a des-arginine (<2368 ng/ml), almost universally (96%) developed the composite renal and mortality end point. C-reactive protein (adjusted hazard ratio, 1.4; 95% CI, 1.1 to 1.8), neutrophil gelatinase-associated lipocalin (adjusted hazard ratio, 2.8; 95% CI, 1.3 to 6.1) and complement 3a desarginine (adjusted hazard ratio, 0.6; 95% CI, 0.4 to 0.96) independently predicted time to the composite end point. CONCLUSIONS: Outpatients with the triad of high soluble TNF receptor-1 and neutrophil gelatinase-associated lipocalin coupled with low complement 3a des-arginine had high adverse event rates over 5-year follow-up. Incorporation of serum biomarkers alongside clinical variables improved prediction of CKD progression and mortality. Our findings require confirmation in larger, more diverse patient cohorts.

Quality of care and practice patterns in anaemia management at specialist kidney clinics in Ireland: a national study.

BACKGROUND: Although anaemia is a common complication of advanced chronic kidney disease (CKD), knowledge of quality of care and management practices in specialist clinics varies. We examined anaemia practices at specialist nephrology clinics within the Irish health system and evaluated the opinions of practicing nephrologists. METHODS: A multicentre cross-sectional study was conducted at specialist nephrology clinics across six geographic regions in Ireland. Clinical characteristics and treatment practices were evaluated in a sample of 530 patients with CKD. An accompanying national survey questionnaire captured opinions and treatment strategies of nephrologists on anaemia management. RESULTS: The prevalence of anaemia [defined as haemoglobin (Hb) <12.0 g/dL] was 37.8%, which increased significantly with advancing CKD (from 21% to 63%; P < 0.01) and varied across clinical sites (from 36% to 62%; P < 0.026). Iron deficiency (ID) was present in 46% of all patients tested and 86% of them were not on treatment. More than 45% of anaemic patients were not tested for ID. Respondents differed in their selection of clinical guidelines, threshold targets for erythropoiesis-stimulating agent (ESA) and intravenous iron therapy and anaemia management algorithms were absent in 47% of the clinics. The unexpectedly low rates of ESA use (4.7%) and iron therapy (10.2%) in clinical practice were in contrast to survey responses where 63% of nephrologists indicated ESA therapy initiation when Hb was <10.0 g/dL and 46% indicated commencement of iron therapy for ferritin <150 ng/mL. CONCLUSION: This study highlights substantial variability in the management of anaemia and ID at specialist nephrology clinics with low testing rates for ID, high rates of anaemia and ID and underutilization of effective treatments. Variability in the adoption and implementation of different clinical guidelines was evident.

Chronic Kidney Disease Severity Is Associated With Selective Expansion of a Distinctive Intermediate Monocyte Subpopulation.

Chronic kidney disease (CKD) affects 11-13% of the world's population and greatly increases risk of atherosclerotic cardiovascular disease (ASCVD) and death. It is characterized by systemic inflammation and disturbances in the blood leukocytes that remain incompletely understood. In particular, abnormalities in the numbers and relative proportions of the three major monocyte subsets-classical, intermediate, and non-classical-are described in CKD and end-stage renal disease. In this study, we characterized absolute numbers of blood leukocyte subtypes in adults with renal function varying from normal to advanced CKD. The primary aim was to identify monocyte subpopulations that associated most closely with current estimated glomerular filtration rate (eGFR) and subsequent rate of eGFR decline. Leucocyte and monocyte populations were enumerated by multi-color flow cytometry of whole blood and peripheral blood mononuclear cell (PBMC) samples from adults with CKD stage 1-5 (n = 154) and healthy adults (n = 33). Multiple-linear regression analyses were performed to identify associations between numbers of leucocyte and monocyte populations and clinical characteristics including eGFR and rate of eGFR decline with adjustment for age and gender. In whole blood, total monocyte and neutrophil, but not lymphocyte, numbers were higher in adults with CKD 1-5 compared to no CKD and were significantly associated with current eGFR even following correction for age. In PBMC, classical and intermediate monocyte numbers were higher in CKD 1-5 but only intermediate monocyte numbers were significantly associated with current eGFR in an age-corrected analysis. When intermediate monocytes were further sub-divided into those with mid- and high-level expression of class II MHC (HLA-DRmid and HLA-DRhi intermediate monocytes) it was found that only DRhi intermediate monocytes were increased in number in CKD 1-5 compared to no CKD and were significantly associated with eGFR independently of age among the total (No CKD + CKD 1-5) study cohort as well as those with established CKD (CKD 1-5 only). Furthermore, blood number of DRhi intermediate monocytes alone proved to be significantly associated with subsequent rate of renal functional decline. Together, our data confirm neutrophil and monocyte subset dysregulation in CKD and identify a distinct subpopulation of intermediate monocytes that is associated with higher rate of loss of kidney function.

Influence of Referral to a Combined Diabetology and Nephrology Clinic on Renal Functional Trends and Metabolic Parameters in Adults With Diabetic Kidney Disease.

OBJECTIVE: To examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD). PATIENTS AND METHODS: All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models. RESULTS: A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: -1.59 vs -3.10 (P=.31) and -1.22 vs -9.39 (P=.06) for T1D; -5.64 vs -3.07 (P=.004) and -10.88 vs -9.94 (P=.70) for T2D; and -6.50 vs +0.91 (P<.001) and -13.28 vs -2.29 (P=.001) for DM with an additional CKD etiology. Glycemic control worsened in those who had T2D, whereas trends in total cholesterol levels improved in those who had T1D. CONCLUSION: After first DRC attendance, the absolute rate of estimated glomerular filtration rate decline remained similar for those who had T1D, but it slowed for those who had T2D or DM with additional CKD etiology. Thus, benefits of combined diabetology and nephrology consultation may vary for different diabetic subpopulations.

Differential impact of smoking on mortality and kidney transplantation among adult Men and Women undergoing dialysis.

BACKGROUND: The extent to which smoking contributes to adverse outcomes among men and women of all ages undergoing dialysis is uncertain. The objective of this study was to determine the differential impact of smoking on risks of mortality and kidney transplantation by age and by sex at dialysis initiation. METHODS: We conducted a population-based cohort of incident U.S dialysis patients (n = 1, 220, 000) from 1995-2010. Age- and sex-specific mortality and kidney transplantation rates were determined for patients with and without a history of cardiovascular disease. Multivariable Cox regression evaluated relative hazard ratios (HR) for death and kidney transplantation at 2 years stratified by atherosclerotic condition, smoking status and age. Analyses were adjusted for demographic characteristics, non-cardiovascular conditions, laboratory variables, socioeconomic and lifestyle factors. RESULTS: The average age was 62.8 (±15) years old, 54 % were male, and the majority was white. During 2-year follow-up, 40.5 % died and 5.7 % were transplanted. Age- and sex-specific mortality rates were significantly higher while transplantation rates were significantly lower for smokers with atherosclerotic conditions than non-smokers (P < 0.01). The adjusted mortality hazards were significantly higher for smokers with pre-existing coronary disease (HR 1.15, 95 % CI (1.11-1.18), stroke (HR 1.21, 1.16-1.27) and peripheral vascular disease (HR = 1.21, 1.17-1.25) compared to non-smokers without these conditions (HR 1.00, referent group). The magnitude of effect was greatest for younger patients than older patients. Contrastingly, the adjusted risks of kidney transplantation were significantly lower for smokers with coronary disease: (HR 0.60, 0.52-0.69), stroke; (HR 0.47, 0.37-0.60), and peripheral arterial disease (HR 0.55, 0.46-0.66) respectively compared to non-smokers without these conditions. CONCLUSIONS: We provide compelling evidence that smoking is associated with adverse clinical outcomes and reduced lifespans among dialysis patients of all ages and sexes. The adverse impact is greatest for younger men and women.

Association of Height with Elevated Mortality Risk in ESRD: Variation by Race and Gender.

The association of adult height with mortality has been extensively investigated in the general population, but little is known about this relationship among dialysis patients. We explored the relationship between height and mortality in a retrospective cohort study of 1,171,842 adults who began dialysis in the United States from 1995 to 2008 and were followed until December 31, 2010. We evaluated height-mortality associations in sex-specific quintiles of increasing height (Q1-Q5) using multivariable Cox regression models adjusted for demographics, comorbid conditions, lifestyle and disability indicators, socioeconomic status, and body weight. For men, compared with the referent quintile (Q1 <167 cm), successive height quintiles had significantly increased hazard ratios (HRs [95% confidence interval]) for mortality: 1.04 (1.02-1.06), 1.08 (1.06-1.10), 1.12 (1.11-1.14), and 1.18 (1.16-1.20) for Q2-Q5, respectively. For women (referent Q1 <155 cm), HRs for mortality were 1.00 (0.99-1.02), 1.05 (1.03-1.06), 1.05 (1.03-1.07), and 1.08 (1.06-1.10) for Q2-Q5, respectively. However, stratification by race showed the pattern of association differed significantly by race (P<0.001 for interaction). For black men, unlike other race groups, height only associated with mortality in Q5, with an HR of 1.06 (1.02-1.09). For black women, HRs for mortality were 0.94 (0.91-0.97), 0.98 (0.95-1.02), 0.96 (0.93-0.99), and 0.99 (0.96-1.02) for Q2-Q5, respectively. These results indicate tallness is associated with higher mortality risks for adults starting dialysis, but this association did not extend to black patients.

Prevalence and variation of Chronic Kidney Disease in the Irish health system: initial findings from the National Kidney Disease Surveillance Programme.

BACKGROUND: Chronic Kidney Disease (CKD) is a major non-communicable chronic disease that is associated with adverse clinical and economic outcomes. Passive surveillance systems are likely to improve efforts for prevention of chronic kidney disease (CKD) and inform national service planning. This study was conducted to determine the overall prevalence of CKD in the Irish health system, assess period trends and explore patterns of variation as part of a novel surveillance initiative. METHODS: We identified 207, 336 adult patients, age 18 and over, with serum creatinine measurements recorded from a provincial database between 2005-2011 in the Northwest of Ireland. Estimated glomerular filtration rates (eGFR) were determined using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation from standardized creatinine measurements and the presence of CKD was defined as eGFR<60 ml/min per 1.73 m2. Age and sex-specific prevalence estimates were determined for each group while generalized estimating equations (GEE) and multivariable logistic regression were used to explore associations using adjusted odds ratios (AOR) and 95% confidence intervals (95% CI). RESULTS: The prevalence of CKD in the health system was 11.8% (95% CI 11.8-12.1); 10.9% in men (10.7-11.1) and 12.6% in women (12.4-12.8). This corresponded to a detection rate of 4.5% (5.1% in women and 3.9% in men). The prevalence of CKD was significantly higher in women than in men (12.6% versus 10.9%, P<0.001), older age groups, and among patients with a history of Acute Kidney Injury (AKI) than without (45.2% versus 10.7%, P<0.0001). Multivariable analysis identified advancing age, female gender, location of medical supervision, county of residence, and AKI as significant determinants of prevalence. CONCLUSION: The prevalence of CKD in the Irish health system is 11.8% corresponding to a detection rate of 4.5% in the general population. Demographic, geographic factors and acute kidney injury episodes are important determinants of disease burden. Passive surveillance of CKD is both feasible and desirable within the Irish health system, and offers huge opportunities for targeted prevention programmes and improved clinical outcomes.

P-value calibration for multiple testing problems in genomics.

Conservative statistical tests are often used in complex multiple testing settings in which computing the type I error may be difficult. In such tests, the reported p-value for a hypothesis can understate the evidence against the null hypothesis and consequently statistical power may be lost. False Discovery Rate adjustments, used in multiple comparison settings, can worsen the unfavorable effect. We present a computationally efficient and test-agnostic calibration technique that can substantially reduce the conservativeness of such tests. As a consequence, a lower sample size might be sufficient to reject the null hypothesis for true alternatives, and experimental costs can be lowered. We apply the calibration technique to the results of DESeq, a popular method for detecting differentially expressed genes from RNA sequencing data. The increase in power may be particularly high in small sample size experiments, often used in preliminary experiments and funding applications.

Granulocyte-macrophage colony-stimulating factor autoantibodies: a marker of aggressive Crohn's disease.

BACKGROUND: Neutralizing autoantibodies (Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn's disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in 2 independent predominantly adult inflammatory bowel disease patient cohorts. METHODS: Serum samples from 742 subjects from the NIDDK IBD Genetics Consortium and 736 subjects from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backward elimination to assess the contribution of GM-CSF Ab levels and established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts. RESULTS: Serum samples from patients with CD expressed significantly higher concentrations of GM-CSF Ab when compared with ulcerative colitis or controls in each cohort. Nonsmokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (P = 0.002). Elevated GM-CSF Ab, ileal disease location, and disease duration more than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD. CONCLUSIONS: The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers.

Differential expression analysis for paired RNA-Seq data.

BACKGROUND: RNA-Seq technology measures the transcript abundance by generating sequence reads and counting their frequencies across different biological conditions. To identify differentially expressed genes between two conditions, it is important to consider the experimental design as well as the distributional property of the data. In many RNA-Seq studies, the expression data are obtained as multiple pairs, e.g., pre- vs. post-treatment samples from the same individual. We seek to incorporate paired structure into analysis. RESULTS: We present a Bayesian hierarchical mixture model for RNA-Seq data to separately account for the variability within and between individuals from a paired data structure. The method assumes a Poisson distribution for the data mixed with a gamma distribution to account variability between pairs. The effect of differential expression is modeled by two-component mixture model. The performance of this approach is examined by simulated and real data. CONCLUSIONS: In this setting, our proposed model provides higher sensitivity than existing methods to detect differential expression. Application to real RNA-Seq data demonstrates the usefulness of this method for detecting expression alteration for genes with low average expression levels or shorter transcript length.

Empirical Bayes correction for the Winner's Curse in genetic association studies.

We consider an Empirical Bayes method to correct for the Winner's Curse phenomenon in genome-wide association studies. Our method utilizes the collective distribution of all odds ratios (ORs) to determine the appropriate correction for a particular single-nucleotide polymorphism (SNP). We can show that this approach is squared error optimal provided that this collective distribution is accurately estimated in its tails. To improve the performance when correcting the OR estimates for the most highly associated SNPs, we develop a second estimator that adaptively combines the Empirical Bayes estimator with a previously considered Conditional Likelihood estimator. The applications of these methods to both simulated and real data suggest improved performance in reducing selection bias.

A new approach for the joint analysis of multiple ChIP-seq libraries with application to histone modification.

Most approaches for analyzing ChIP-Seq data are focused on inferring exact protein binding sites from a single library. However, frequently multiple ChIP-Seq libraries derived from differing cell lines or tissue types from the same individual may be available. In such a situation, a separate analysis for each tissue or cell line may be inefficient. Here, we describe a novel method to analyze such data that intelligently uses the joint information from multiple related ChIP-Seq libraries. We present our method as a two-stage procedure. First, separate single cell line analysis is performed for each cell line. Here, we use a novel mixture regression approach to infer the subset of genes that are most likely to be involved in protein binding in each cell line. In the second step, we combine the separate single cell line analyses using an Empirical Bayes algorithm that implicitly incorporates inter-cell line correlation. We demonstrate the usefulness of our method using both simulated data, as well as real H3K4me3 and H3K27me3 histone methylation libraries.