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A letter to the editor is presented about a study on the link of oral sodium phosphate use to chronic kidney disease (CKD).

Background Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). Methods We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. Results The mean eGFR slope was 2.2 (1.4) and −5.1 (1.2) mL/min/1.73 m2 in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E−05 to 9.5E−05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E−03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Conclusions Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD. [ABSTRACT FROM AUTHOR]

We conducted a case-control study of adults with bacteremic pneumococcal pneumonia to identify factors associated with macrolide resistance. Study participants were identified through population-based surveillance in a 5-county region surrounding Philadelphia. Forty-three hospitals contributed 444 patients, who were interviewed by telephone regarding potential risk factors. In multivariable analyses, prior exposure to a macrolide antimicrobial agent (odds ratio [OR] 2.8), prior flu vaccination (OR 2.0), and Hispanic ethnicity (OR 4.1) were independently associated with an increased probability of macrolide resistance, and a history of stroke was independently associated with a decreased probability of macrolide resistance (OR 0.2). Fifty-five percent of patients with macrolide-resistant infections reported no antimicrobial drug exposure in the preceding 6 months. Among patients who reported taking antimicrobial agents in the 6 months preceding infection, failure to complete the course of prescribed drugs was associated with an increased probability of macrolide resistance (OR 3.4). [ABSTRACT FROM AUTHOR]

Abstract: Invasive pneumococcal disease in adults may be declining, reflecting a form of herd protection from a new pediatric pneumococcal conjugate vaccine. Our aim was to determine whether vaccination of children protects adults in the same home from bacteremic pneumococcal pneumonia. We conducted a case–control study with 43 participating hospitals across a five-county region in Pennsylvania. Eligible cases were adults with bacteremic pneumococcal pneumonia identified by the microbiology laboratories at participating hospitals. Controls were healthy adults from the region identified through random digit dialing. Cases and controls were interviewed by telephone. We analyzed vaccine protection in those adults who reported living in homes with at least one child ≤6 years of age. From April 2002 through June 2004, there was a significant decline in the proportion of adult pneumococcal bacteremia due to any of the seven serotypes in the conjugate vaccine (p =0.006). Within this time period, 17% of cases and controls reported living in homes with at least one child ≤6 years of age. In adjusted analysis, vaccination of the youngest child in the home was associated with an 80% reduction in the odds of bacteremic pneumococcal pneumonia among adults with children in the home (OR=0.2, 95% CI 0.1–0.8). We conclude that introduction of a pneumococcal conjugate vaccine for children has reduced the population rate of adult pneumococcal bacteremia due to vaccine serotypes and is associated with a reduced risk of bacteremic pneumococcal pneumonia for adults with children in the home. [Copyright &y& Elsevier]

This article addresses unique causal issues in the context of a randomized study on improving adherence to best practice guidelines by primary care physicians (PCP's) in treating their depressed patients. The study assessed an encouragement strategy to improve PCP guideline adherence. In this context, we compare two causal approaches: the conditional-compliance (CC) Bayesian latent class and the conditional-observable (CO) structural mean model methods. The CC methods estimate contrasts between randomized encouragement and no-encouragement arms [intent-to-treat (ITT) estimand] given latent PCP guideline complier classes. The CO methods estimate contrasts between PCP guideline adherence and nonadherence conditions (as-treated estimand) given observed PCP adherence status. The CC ITT estimand for patients with PCP compliers equals the CO as-treated estimand depending on assumptions. One such assumption pertains to the absence of physician defiers, who do the opposite of what they are encouraged to do in treating patients for depression. We relate these two estimands to each other in our clinical context when the no-defter assumption is not plausible. In other contexts, previous statistical literature has appropriately assumed the absence of defiers. However, indications in the behavioral literature, anecdotal evidence in the study, and results from the data analysis and simulations suggest that defiers do exist in the context of physician-based interventions in primary care. Both simulation and empirical results show that even with a small estimated proportion of defiers under Bayesian model assumptions, inference is sensitive to different assumptions about this class of PCP noncompliers. [ABSTRACT FROM AUTHOR]

Israni AK, Weng FL, Cen Y-Y, Joffe M, Kamoun M, Feldman HI. Electronically measured adherence to immunosuppressive medications and kidney function after deceased donor kidney transplantation. Clin Transplant 2011: 25: E124-E131. © 2010 John Wiley & Sons A/S. Non-adherence with immunosuppressive medications can result in allograft rejection and eventually allograft loss. In a racially diverse population, we utilized microelectronic cap monitors to determine the association of adherence with a single immunosuppressive medication and kidney allograft outcomes post-transplantation. This prospective cohort study enrolled 243 patients from eight transplant centers to provide adherence and kidney allograft outcomes data. To determine the association of adherence with change in estimated glomerular filtration rate (eGFR), we fit mixed effects models with the outcome being change in eGFR over time. We also fit Cox proportional hazards models to determine the association of adherence with time to persistent 25% and 50% decline in eGFR. The distribution of adherence post-transplant was as follows: 164 (68%), 49 (20%), and 30 (12%) had >85-100%, 50-85%, and <50% adherence, respectively. Seventy-nine (33%) and 36 (15%) of the subjects experienced a persistent 25% decline in eGFR or allograft loss and 50% decline in eGFR or allograft loss during follow-up. Adherence was not associated with acute rejection or 25% decline or 50% decline in eGFR. In the adjusted and unadjusted model, adherence and black race were not associated with change in eGFR over time. Non-adherence with a single immunosuppressive medication was not associated with kidney allograft outcomes. [ABSTRACT FROM AUTHOR]

Delayed allograft function (DGF) is a common adverse event in postrenal transplantation. The etiology of DGF is thought to include both nonimmunologic (donor age, cold ischemia time, and recipient race) and immunologic factors. We examined the association of DGF with amino acid mismatches at 66 variable sites of the HLA-A molecule in a prospective cohort study of 697 renal transplant recipients of deceased donors. Using a multivariate logistic regression model adjusted for nonimmunologic risk factors, we show that combinations of a few amino acid mismatches at crucial sites of HLA-A molecules were associated with DGF. In Caucasian recipients, a mismatch at position 62, 95, or 163, all known to be functionally important within the antigen recognition site, was associated with an increased risk for DGF. Furthermore, a decreased risk for DGF was associated with a mismatch at HLA-A family-specific sites (149, 184, 193, or 246), indicating that evolutionary features of HLA-A polymorphism separating HLA-A families and lineages among donor-recipient pairs may correlate with the magnitude of alloreactivity influencing the development of DGF. These findings suggest that amino acid polymorphisms at functionally important positions at the antigen recognition site of the HLA-A molecule have a significant influence on DGF. [ABSTRACT FROM AUTHOR]

Background: The unique distribution of the alleles for the Duffy antigen receptor complex (DARC) that binds to chemokines may be associated with the rates of acute rejection and delayed allograft function (DGF) among African Americans.Methods: A prospective, multicenter cohort study enrolled 222 African American recipients of cadaveric renal allografts from eight adult transplant centers. Subjects were typed by allele-specific polymerase chain reaction (ASPCR) for the polymorphism at position 535 that determines the level of transcription. Associations of DARC genotypes were examined in Cox hazards models with episodes of acute rejection and in logistic regression models with the development of DGF.Results: FyB Null homozygosity was observed among 67% of the recipients. Fifteen percent of the study cohort experienced at least one episode of acute rejection, and the incidence of DGF was 42.5%. The number of FyB Null alleles and FyB Null homozygosity had no detectable association with the rate of acute rejection (P > 0.50) or with the development of DGF (P > 0.50).Conclusion: The susceptibility of African American recipients to acute rejection and to DGF was not confirmed to be associated with DARC alleles or genotype. Future studies should exclude a potential role of donor-related DARC in transplant outcomes. [ABSTRACT FROM AUTHOR]

Background: Previous studies have reported a high prevalence of mitral-valve prolapse among patients with embolic stroke (28 to 40 percent), especially among young patients (those ≤45 years old); this finding has practical implications for prophylaxis. However, diagnostic criteria for prolapse have changed and are now based on three-dimensional analysis of the shape of the valve; use of the current criteria reduces markedly the frequency of such a diagnosis and increases its specificity. Previously described complications must therefore be reconsidered. Methods: In a case–control study, we reviewed data on 213 consecutive patients 45 years of age or younger with documented ischemic stroke or transient ischemic attack between 1985 and 1995; they underwent complete neurologic and echocardiographic evaluations. The prevalence of prolapse in these patients was compared with that in 263 control subjects without known heart disease, who were referred to our institution for assessment of ventricular function before receiving chemotherapy. Results: Mitral-valve prolapse was present in 4 of the 213 young patients with stroke (1.9 percent), as compared with 7 of the 263 controls (2.7 percent); prolapse was present in 2 of 71 patients (2.8 percent) with otherwise unexplained stroke. The crude odds ratio for mitral-valve prolapse among the patients who had strokes, as compared with those who did not have strokes, was 0.70 (95 percent confidence interval, 0.15 to 2.80; P=0.80); after adjustment for age and sex, the odds ratio was 0.59 (95 percent confidence interval, 0.12 to 2.50; P=0.62). Conclusions: Mitral-valve prolapse is considerably less common than previously reported among young patients with stroke or transient ischemic attack, including unexplained stroke, and no more common than among controls. Using more specific and currently accepted echocardiographic criteria, therefore, we could not demonstrate an association between the presence of mitral-valve prolapse and acute ischemic neurologic events in young people. (N Engl J Med 1999;341:8-13.) [ABSTRACT FROM AUTHOR]

Background: Observational studies are frequently used to estimate the comparative effectiveness of different colorectal cancer (CRC) screening methods due to the practical limitations and time needed to conduct large clinical trials. However, time-varying confounders, e.g. polyp detection in the last screening, can bias statistical results. Recently, generalized methods, or G-methods, have been used for the analysis of observational studies of CRC screening, given their ability to account for such time-varying confounders. Discretization, or the process of converting continuous functions into discrete counterparts, is required for G-methods when the treatment and outcomes are assessed at a continuous scale., Development: This paper evaluates the interplay between time-varying confounding and discretization, which can induce bias in assessing screening effectiveness. We investigate this bias in evaluating the effect of different CRC screening methods that differ from each other in typical screening frequency., Application: First, using theory, we establish the direction of the bias. Then, we use simulations of hypothetical settings to study the bias magnitude for varying levels of discretization, frequency of screening and length of the study period. We develop a method to assess possible bias due to coarsening in simulated situations., Conclusions: The proposed method can inform future studies of screening effectiveness, especially for CRC, by determining the choice of interval lengths where data are discretized to minimize bias due to coarsening while balancing computational costs., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Introduction : We evaluated visual acuity (VA) over 5 years in a subspecialty noninfectious uveitis population. Methods : Retrospective data from 5,530 noninfectious uveitis patients with anterior, intermediate, posterior or panuveitis were abstracted by expert reviewers. Mean VA was calculated using inverse probability of censoring weighting to account for losses to follow-up. Results : Patients were a median of 41 years old, 65% female, and 73% white. Initial mean VA was worse among panuveitis (20/84) than posterior (20/64), intermediate (20/47), and anterior (20/37) uveitides. On average, mean VA improved by 0.62, 0.51, 0.37, and 0.26 logMAR-equivalent lines over 2 years, respectively (each P < .001), then remained stable, except posterior uveitis mean VA worsened to initial levels. Conclusion : Mean VA of uveitic eyes improved and, typically, improvement was sustained under uveitis subspecialty care. Because VA tends to improve under tertiary care, mean VA change appears a better outcome for clinical studies than time-to-loss of VA.

Purpose: To compare mycophenolate mofetil (MMF) to methotrexate (MTX) as corticosteroid-sparing therapy for ocular inflammatory diseases., Design: Retrospective analysis of cohort study data., Methods: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics were obtained via medical record review. The study included 352 patients who were taking single-agent immunosuppression with MTX or MMF at 4 tertiary uveitis clinics. Marginal structural models (MSM)-derived statistical weighting created a virtual population with covariates and censoring patterns balanced across alternative treatments. With this methodological approach, the results estimate what would have happened had none of the patients stopped their treatment. Survival analysis with stabilized MSM-derived weights simulated a clinical trial comparing MMF vs MTX for noninfectious inflammatory eye disorders. The primary outcome was complete control of inflammation on prednisone ≤10 mg/day, sustained for ≥30 days., Results: The time to success was shorter (more favorable) for MMF than MTX (hazard ratio = 0.68, 95% confidence interval: 0.46-0.99). Adjusting for covariates, the proportion achieving success was higher at every point in time for MMF than MTX from 2 to 8 months, then converges at 9 months. The onset of corticosteroid-sparing success took more than 3 months for most patients in both groups. Outcomes of treatment (MMF vs MTX) were similar across all anatomic sites of inflammation. The incidence of stopping therapy for toxicity was similar in both groups., Conclusions: Our results suggest that, on average, MMF may be faster than MTX in achieving corticosteroid-sparing success in ocular inflammatory diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives: CKD is a global public health problem with significant mortality and morbidity., Design, Setting, Participants, & Measurements: We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants., Results: Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant., Conclusions: Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD., (Copyright © 2016 by the American Society of Nephrology.)

Background: Various indicators of progression of chronic kidney disease (CKD) have been used as outcomes in clinical research studies. The effect of using varying measures on the association of risk factors with CKD progression has not been well characterized., Study Design: Prospective cohort study., Setting & Participants: The Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,939) enrolled men and women with mild to moderate CKD, 48% of whom had diabetes and 42% were self-reported black race., Predictors: Age, race, sex, diabetes, baseline estimated glomerular filtration rate (eGFR), proteinuria, and other established CKD risk factors., Outcomes: Death, end-stage renal disease (ESRD), and eGFR events, including: (1) eGFR halving, (2) eGFR<15mL/min/1.73m(2), (3) eGFR halving and <15mL/min/1.73m(2), (4) eGFR decrease of 20mL/min/1.73m(2), (5) eGFR halving or decrease of 20mL/min/1.73m(2), and (6) eGFR decrease of 25% and change in CKD stage., Results: Mean entry eGFR was 44.9mL/min/1.73m(2). Annual rates of death, ESRD, and eGFR halving were 2.5%, 4.0%, and 6.1%, respectively, during an average follow-up of 5.4 years. Associations between risk factors and ESRD and eGFR events were similar across different definitions. However, these associations were substantially different from those with death. HRs for ESRD, eGFR halving, and death in the highest compared to the lowest proteinuria category were 11.83 (95% CI, 8.40-16.65), 11.19 (95% CI, 8.53-14.68), and 1.47 (95% CI, 1.10-1.96), respectively., Limitations: Participants may not be representative of the entire CKD population., Conclusions: Using ESRD or eGFR events, but not death, in the definition of kidney disease outcomes is appropriate in follow-up studies to identify risk factors for CKD progression., (Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.)

Purpose: Erythropoietin (EPO) improves measures of quality of life and reduces transfusions. Clinical trials have reported higher mortality associated with higher hemoglobin targets in varied clinical settings, making difficult the selection of erythropoiesis stimulation strategies in end-stage kidney disease. Observational studies distinguishing an effect of EPO from underlying conditions are challenging, but promise insights relevant to real-world settings., Methods: Using data from the United States Renal Data System, we performed a retrospective cohort study of hemodialysis patients treated between 2000 and 2004. 409 364 Medicare insured patients receiving hemodialysis therapy as of January 2000 or who began dialysis after January 2000 and survived >6 months were studied. We examined the association of EPO dose in any given month with death over subsequent follow-up., Results: Within each hematocrit group (<30%, 30%–< 33%, 33%–< 36%, 36%–< 39% and >39%), the hazard ratios comparing the 80th percentile to the median EPO dose were 0.88 (95% CI: [0.87–0.90]), 0.94 ([0.93–0.94]), 0.98 ([0.98–0.99]), 1.06 ([1.05–1.06]) and 1.08 ([1.07–1.09]), respectively. Within the highest hematocrit group, the association of a high EPO dose with elevated mortality was attenuated over time. Among patients with malignancy or indications of EPO resistance, the association of higher EPO dose with lower mortality was attenuated when hematocrit was low, while its association with higher mortality was stronger when hematocrit was high., Conclusions: These analyses demonstrate a complex relationship between EPO dosing and mortality, suggesting a possible beneficial effect among severely anemic hemodialysis patients, but possible harm when administered to individuals with higher hematocrit levels.

Background: Glomerular filtration rate (GFR) is considered the best measure of kidney function, but repeated assessment is not feasible in most research studies., Study Design: Cross-sectional study of 1,433 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (ie, the GFR subcohort) to derive an internal GFR estimating equation using a split-sample approach., Setting & Participants: Adults from 7 US metropolitan areas with mild to moderate chronic kidney disease; 48% had diabetes and 37% were black., Index Test: CRIC GFR estimating equation., Reference Test or Outcome: Urinary (125)I-iothalamate clearance testing (measured GFR [mGFR])., Other Measurements: Laboratory measures, including serum creatinine and cystatin C, and anthropometrics., Results: In the validation data set, the model that included serum creatinine level, serum cystatin C level, age, sex, and race was the most parsimonious and similarly predictive of mGFR compared with a model additionally including bioelectrical impedance analysis phase angle, CRIC clinical center, and 24-hour urinary creatinine excretion. Specifically, root mean square errors for the separate models were 0.207 versus 0.202, respectively. Performance of the CRIC GFR estimating equation was most accurate for the subgroups of younger participants, men, nonblacks, non-Hispanics, those without diabetes, those with body mass index <30 kg/m(2), those with higher 24-hour urine creatinine excretion, those with lower high-sensitivity C-reactive protein levels, and those with higher mGFRs., Limitations: Urinary clearance of (125)I-iothalamate is an imperfect measure of true GFR; cystatin C level is not standardized to certified reference material; lack of external validation; small sample sizes limit analyses of subgroup-specific predictors., Conclusions: The CRIC GFR estimating equation predicts mGFR accurately in the CRIC cohort using serum creatinine and cystatin C levels, age, sex, and race. Its performance was best in younger and healthier participants., (Copyright © 2012 National Kidney Foundation, Inc. All rights reserved.)

In principle, G-estimation is an attractive approach for dealing with confounding by variables affected by treatment. It has rarely been applied for estimation of the effects of treatment on failure-time outcomes. Part of this is due to artificial censoring, an analytic device which considers some subjects who actually were observed to fail as if they were censored. Artificial censoring leads to a lack of smoothness in the estimating function, which can pose problems in variance estimation and in optimization. It also can lead to failure to have solutions to the usual estimating functions, which then raises questions about the appropriate criteria for optimization. To improve performance of the optimization procedures, we consider approaches for reducing the amount of artificial censoring, propose the substitution of smooth for indicator functions, and propose the use of estimating functions scaled to a measure of the information in the data; we evaluate performance of these approaches using simulation. We also consider appropriate optimization criteria in the presence of information loss due to artificial censoring. We motivate and illustrate our approaches using observational data on the effect of erythropoietin on mortality among subjects on hemodialysis., (© 2011, The International Biometric Society.)

We review the concept of time-dependent confounding by using the example in paper "Comparative effectiveness of individual angiotensin receptor blockers on risk of mortality in patients with chronic heart failure" by Desai et al. and illustrate how to adjust for it by using inverse probability of treatment weighting through a simulated example. We discuss a few subtle issues that arise in specification of the model for treatment required to fit marginal structural models (MSMs) and in specification of the structural model for the outcome. We discuss the differences between the effects estimated in MSMs and intention-to-treat effects estimated in randomized trials, followed by an outline of some limitations of MSMs.

In case-control research where there are multiple case groups, standard analyses fail to make use of all available information. Multiple events case-control (MECC) studies provide a new approach to sampling from a cohort and are useful when it is desired to study multiple types of events in the cohort. In this design, subjects in the cohort who develop any event of interest are sampled, as well as a fraction of the remaining subjects. We show that a simple case-control analysis of data arising from MECC studies is biased and develop three general estimating-equation-based approaches to analyzing data from these studies. We conduct simulation studies to compare the efficiency of the various MECC analyses with each other and with the corresponding conventional analyses. It is shown that the gain in efficiency by using the new design is substantial in many situations. We demonstrate the application of our approach to a nested case-control study of the effect of oral sodium phosphate use on chronic kidney injury with multiple case definitions., (© 2009, The International Biometric Society.)

Findings from randomized controlled trials examining the efficacy of therapy with erythropoiesis-stimulating agents (ESAs) to normalize hemoglobin levels in patients with chronic kidney disease or kidney failure have raised questions regarding the safety of this class of drugs. However, no trial to date has specifically assessed the safety of ESA-dosing algorithms used to achieve the lower hemoglobin targets typically using in clinical practice. Although a wealth of nonexperimental data is available for dialysis patients, analyses based on these data are more susceptible to confounding bias than randomized controlled trials. Conducting valid pharmacoepidemiologic studies of drug effects in hemodialysis patients is complicated by the extent of their comorbidities, frequent hospitalizations, various concomitant medications, and an exceedingly high mortality rate. The need for greater ESA doses for the treatment of anemia in sicker patients potentially and plausibly generates confounding by indication, the control of which is complicated by the presence of time-dependent confounding. Here, we describe sources of bias in nonexperimental studies of ESA therapy in hemodialysis patients and critically appraise analytical methods that may help minimize bias in such studies.

Background: Many studies suggest that chronic kidney disease (CKD) care is suboptimal in the United States. However, it is not known whether knowledge of CKD management in primary care physicians (PCPs) might have an important role in the suboptimal care and whether PCP characteristics are associated with having adequate knowledge., Study Design: Cross-sectional study., Setting & Participants: Self-administered questionnaire sent to a random sample of 1,550 US PCPs in February 2007., Predictor or Factor: PCP characteristics, including age, sex, degree (MD versus DO), primary specialty, board certification, patient volume, percentage of time in patient care spent in the inpatient versus outpatient setting, and number of patients referred to nephrologists in a month., Outcomes & Measurements: Regression analyses of the association between physician characteristics and overall physician knowledge of CKD management, as well as individual subdomains of CKD knowledge related to recognition of CKD and management of hypertension in the setting of CKD., Results: 470 of 1,453 (32.4%) eligible PCPs returned a completed survey. PCPs show significant variation in their ability to recognize CKD stages 2 to 4, but most have appropriate blood pressure goals in patients with CKD and are knowledgeable of the role of angiotensin-converting enzyme inhibitors in managing proteinuria. For each 10-year increase in age, the odds of showing satisfactory knowledge of CKD management decreased by 26% (odds ratio, 0.74; 95% confidence interval, 0.60 to 0.92). PCPs with the primary specialty of internal medicine had a more than 3-fold greater odds of showing a satisfactory level of knowledge compared with family practice specialists (odds ratio, 3.40; 95% confidence interval, 2.17 to 5.32)., Limitations: The study findings are limited by the potential presence of nonresponse bias, information bias, and results suggesting there are multiple knowledge subdomains that perhaps are not additive., Conclusion: There is need to improve CKD knowledge in PCPs, especially regarding recognition of CKD at an early stage.

Summary: Four major frameworks have been developed for evaluating surrogate markers in randomized trials: one based on conditional independence of observable variables, another based on direct and indirect effects, a third based on a meta-analysis, and a fourth based on principal stratification. The first two of these fit into a paradigm we call the causal-effects (CE) paradigm, in which, for a good surrogate, the effect of treatment on the surrogate, combined with the effect of the surrogate on the clinical outcome, allow prediction of the effect of the treatment on the clinical outcome. The last two approaches fall into the causal-association (CA) paradigm, in which the effect of the treatment on the surrogate is associated with its effect on the clinical outcome. We consider the CE paradigm first, and consider identifying assumptions and some simple estimation procedures; we then consider the CA paradigm. We examine the relationships among these approaches and associated estimators. We perform a small simulation study to illustrate properties of the various estimators under different scenarios, and conclude with a discussion of the applicability of both paradigms.

Background: Cardiovascular disease is a leading cause of death among renal transplant recipients. Aortic calcification is associated with increased mortality in dialysis subjects. The significance of aortic calcification among renal transplant recipients is unknown. Our objective was to prospectively examine the association of aortic calcification with cardiovascular events and all-cause mortality among asymptomatic incident renal transplant recipients., Methods: One hundred and twelve renal transplant recipients underwent electron beam computed tomography. Aortic calcification was scored by the Agatston method. The mean follow-up time was 5.1 years. Cardiovascular events (heart failure, coronary artery disease, peripheral arterial disease and stroke) and all-cause mortality were recorded., Results: The cohort consisted of 62% Caucasians, 38% African Americans and 62% male gender. The mean age was 49.0 +/- 12.5 years. Thirty-four percent had aortic calcification. During follow-up, 12 cardiovascular events and 10 deaths were recorded. Subjects with aortic calcification had more cardiovascular events compared to those without aortic calcification (23.7 versus 4.1%, P = 0.001). Recipients with aortic calcification had higher mortality compared to those without aortic calcification but it did not reach statistical significance (15.8 versus 5.4%, P = 0.07). The univariate hazard ratio of aortic calcification score in a proportional hazard Cox model to assess event-free survival was 1.15 (1.04-1.27, P = 0.01). Diabetes and aortic calcification score were independently associated with survival. In addition to the predictors above, dialysis vintage was an independent predictor for combined future cardiovascular event and mortality., Conclusions: In conclusion, aortic calcification is prevalent among renal transplant recipients and is predictive of future cardiovascular events. Aortic calcification is easily identified by non-invasive testing, and should be considered when assessing cardiovascular risk in asymptomatic renal transplant recipients.

Background and Objectives: Anemia is a common and early complication of nondialysis chronic kidney disease (CKD). One contributing factor is iron deficiency, which may be particularly problematic during erythropoietin replacement therapy. The aim of this study was to examine the prevalence of iron deficiency in nondialysis CKD., Design, Setting, Participants, & Measurements: The National Health and Nutritional Examination Survey (NHANES) data for NHANES III (1988 to 1994) and subsequent NHANES 2-yr datasets, 1999 to 2000, 2001 to 2002, and 2003 to 2004 were analyzed for individuals >18 yr old., Results: It was found that low levels of iron tests [either serum ferritin < 100 ng/ml or transferrin saturation (TSAT) < 20%] were present in most patients with reduced creatinine clearance (CrCl). The percentage of low iron tests was higher among women than men, present in 57.8 to 58.8% of men and 69.9 to 72.8% of women (P < 0.001). With declining levels of CrCl, in women, TSAT levels decreased, whereas, surprisingly, serum ferritin tended to progressively increase. The percentage of anemic subjects increased progressively with declining quartiles of TSAT but was unrelated to serum ferritin quartiles., Conclusions: It was found that low levels of iron tests, following National Kidney Foundation/Kidney Disease Outcomes Quality Initiative guidelines (either serum ferritin < 100 ng/ml or TSAT < 20%) were present in most patients with reduced CrCl.

Background: Blood pressure variability (BPV) is one putative risk factor for cardiovascular disease and mortality in hemodialysis patients. The purposes of this study are to identify a suitable metric of long-term BPV in this population and determine whether an association between BPV and all-cause mortality exists., Study Design: Retrospective cohort study., Settings & Participants: Patients from the Accelerated Mortality on Renal Replacement (ArMORR) cohort who were adult, incident to hemodialysis at any Fresenius Medical Care unit between June 2004 and August 2005, and had suitable blood pressure data were studied (n = 6,961)., Predictor: Predialysis blood pressures measured between dialysis days 91 and 180 were used to determine each patient's absolute level of, trend in (slope over time), and variability in blood pressure., Outcome: All-cause mortality beginning immediately after day 180 and continuing through day 365 or until censoring (median follow-up, 185 days)., Results: Of the 4 candidate BPV metrics, only average residual-intercept ratio adequately distinguished BPV from absolute blood pressure level and temporal blood pressure trend. In the primary analysis, each SD increase in systolic and diastolic BPV was associated with adjusted hazard ratios for all-cause mortality of 1.13 (95% confidence interval, 1.03 to 1.23) and 1.15 (95% confidence interval, 1.06 to 1.26), respectively. Results were consistent across multiple sensitivity analyses in which inclusion and exclusion criteria and timing of blood pressure measurements were varied., Limitations: Contingency of results on the validity of mathematic description of BPV; potential for misclassification bias and residual confounding., Conclusions: Provided the mathematical descriptions of BPV are valid, the data suggest that systolic and diastolic BPV is associated with all-cause mortality in incident hemodialysis patients. Additional study is necessary to confirm and generalize findings, assess the interplay between systolic and diastolic BPV, and assess causality.

Background: Delayed renal allograft survival (delayed graft function [DGF]) after deceased donor kidney transplantation is associated with an increased risk of allograft loss. Inflammatory response and apoptosis are associated with increased risk of DGF., Study Design: Cross-sectional study., Setting & Participants: We first recruited 616 recipients of kidneys from 512 deceased kidney donors, and donor DNA was genotyped. These recipients, who were included in a prospective cohort study of 9 transplant centers in the Delaware Valley region, had their DGF outcome obtained through medical record abstraction. We then identified the recipient (n = 349) of the contralateral deceased kidney donor, if not part of the cohort, through the US Renal Data System registry. The final cohort consisted of 965 recipients of deceased donor kidneys from 512 donors., Predictors: Donor single-nucleotide polymorphisms in genes for tumor necrosis factor alpha (TNF), transforming growth factor beta1 (TGFB1), interleukin 10 (IL10), p53 (TP53), and heme oxygenase 1 (HMOX1)., Outcomes: DGF, defined as the need for dialysis therapy in the first week posttransplantation. Secondary outcomes included acute rejection and estimated glomerular filtration rate., Measurements: Information for DGF, acute rejection, and estimated glomerular filtration rate for recipients in the Delaware Valley Cohort was obtained through medical record abstraction. For other recipients, information for DGF was obtained from United Network for Organ Sharing forms and Centers for Medicare & Medicaid Services claims in the US Renal Data System registry., Results: No association was detected between the TGFB1, IL10, TP53, and HMOX1 genes and DGF. The G allele of the TNF polymorphism rs3093662 was associated with DGF in an adjusted analysis (odds ratio, 1.85 compared with A allele; 95% confidence interval, 1.16 to 2.96; P = 0.01). However, this association did not achieve statistical significance after adjusting for multiple comparisons., Limitations: Inadequate sample size for infrequent genotypes and multiple comparisons., Conclusion: Because of the low frequency of donor single-nucleotide polymorphisms of interest, a larger sample size and replication are necessary to confirm these findings on the association of donor genotypes with DGF.

Delayed time to antibiotic administration has been linked with higher mortality for patients with community-acquired pneumonia, but the impact of antibiotic resistance on clinical outcomes has been controversial. In the current study we assess the combined impact of antibiotic resistance and antibiotic timing on outcomes, including inhospital mortality, complications, length of stay, and time to stability, for patients hospitalized with community-acquired bacteremic pneumococcal pneumonia. We conducted a retrospective cohort study in 43 hospitals in the Southeastern Pennsylvania region from 2001 to 2004. Eligible adult patients had pneumococcal bacteremia and radiographic evidence of pneumonia. Outcomes were assessed based on medical record review. Multivariable regression was used to adjust for severity of illness and sequentially assess the impact of antibiotic resistance and time to active antibiotic therapy. The overall inhospital mortality was 10%. Overall, levels of macrolide, cephalosporin, and fluoroquinolone resistance were low and did not adversely impact the time to administration of active antibiotic therapy. Receipt of at least 1 active antibiotic within 4 hours was associated with reduced mortality (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.2-1.0) and shortened length of stay (OR, 0.77; CI, 0.6-1.0) but did not reduce the risk of other adverse outcomes. We conclude that early antibiotic administration reduces the risks of mortality in patients with bacteremic pneumococcal pneumonia. Current patterns of drug resistance did not lead to delays in administration of active antimicrobial therapy.

Hemoglobin levels vary substantially over time in hemodialysis patients, and this variability may portend poor outcomes. For a given patient, hemoglobin concentration over time can be described by absolute levels, rate of change, or by the difference between observed level and expected level based on the preceding trend (i.e., seemingly random variability). We investigated the independent associations of these different methods of describing hemoglobin over time with mortality in a retrospective cohort of 34,963 hemodialysis patients. Hemoglobin concentration over time was modeled with linear regression for each subject, and the model was then used to define the subject's absolute level of hemoglobin (intercept), temporal trend in hemoglobin (slope), and hemoglobin variability (residual standard deviation). Survival analyses indicated that each 1g/dl increase in the residual standard deviation was associated with a 33% increase in rate of death, even after adjusting for multiple covariates. Patient characteristics accounted for very little of the variation in our hemoglobin variability metric (R2 = 0.019). We conclude that greater hemoglobin variability is independently associated with higher mortality.

Missing data are often imputed for analysis, but a single imputation may be inaccurate when performing feature selection in mining data. Feature selection procedures applied to multiply imputed data demonstrate this phenomenon and suggest that multiple imputation is an important adjunct to knowledge discovery.

The use of propensity scores to adjust for measured confounding factors has become increasingly popular in cohort studies. However, their use in case-control and case-cohort studies has received little attention. The authors present some theory on the estimation and use of propensity scores in case-control and case-cohort studies and present the results of simulation studies that examine whether large-sample expectations are realized in studies of typical size. The application of propensity scores is less straightforward in case-control and case-cohort studies than in cohort studies. The authors' simulations revealed two potentially important issues. First, when using several potential approaches, there is artifactual effect modification of the odds ratio by level of propensity score. The magnitude of this phenomenon decreases as the sample size increases. Second, several potential approaches produce estimated propensity scores that do not converge to the true value as sample size increases and, thus, can fail to adjust fully for measured confounding factors. However, the magnitude of residual confounding appeared modest in our simulations. Researchers considering using propensity scores in case-control or case-cohort studies should consider the potential for artifactual effect modification and their reduced ability to control for potential confounding factors.

Purpose: The purpose of this study was to determine the effects of international teleradiology attending radiologist coverage (ITARC) of emergency examinations on radiology residents' perceptions of night call., Methods: A survey was administered at 2 different radiology residency programs that have attending radiologists who cover the night shift via teleradiology from Israel 5 nights per week. The survey consisted of 12 questions concerning residents' education and anxiety during on-call shifts and the effects of ITARC on these aspects of residency training. The questions were answered on a scale ranging from 1 to 5, with 3 being neutral., Results: The radiology residents felt that ITARC improved the on-call learning experience (score = 3.7; 1 = much worse, 5 = much improved). The residents felt neutral about the statements "Review of cases with the attending radiologist over the telephone is comparable educationally to having the attending radiologist in person at the workstation" (score = 3.0) and "Having an attending radiologist easily available diminishes the need for me to commit to a diagnosis on my own and is therefore detrimental to my education" (score = 2.9; 1 = strongly disagree, 5 = strongly agree). The residents' stress levels on call were high without ITARC (score = 1.8; 1 = very high, 5 = very low) and moderate with ITARC (score = 2.7). The residents' anxiety levels before a night on call were moderate without ITARC (score = 2.9; 1 = very high, 5 = very low) and low with ITARC (score = 3.7)., Conclusions: Radiology residents felt that ITARC improved their educational experience. International teleradiology attending radiologist coverage also decreased radiology residents' stress and anxiety related to on-call shifts.

Estimating the effects of a toxin on fetal development in animal models such as mice can be problematic, because the number of pups that develop and survive until birth may simultaneously affect developmental outcomes such as birth weight and be affected by the introduction of a toxin into the fetal environment. Also, comparing pups that survived until birth at a high dose of the toxin with pups that survived at low doses may underestimate the effect of the toxin, because the lower dose means include the less healthy pups that would not survive if exposed to a higher level of toxin. We consider this problem in a potential outcomes framework that defines the effect of the dose on the outcome as the difference between what the outcome would have been for a pup had the dam in which the pup develops been exposed to dose level Z=z* rather than dose level Z=z. To disentangle the direct effect of dose from the effect of litter size, we focus on effects defined within principal strata that are a function of the survival status of the pups at each of the possible dose levels. A unique contribution to the potential outcomes literature is that we allow the outcome for a subject to be dependent on the principal stratum to which other subjects within a cluster belong.

Background: The objective of this study was to gain insight into the associations of anemia with mortality among maintenance hemodialysis (HD) patients and patient subgroups by an analysis that more comprehensively represents hemoglobin (Hb) level, morbidity, and treatment characteristics over time than was possible in prior observational studies., Methods: A cohort study was conducted among 5517 subjects in the American arm of the Dialysis Outcomes and Practice Patterns Study Phase I. We used proportional hazard analysis to model all-cause mortality as a function of Hb level measured 1, 3, and 6 months previously. Forty-five potentially confounding patient-level characteristics were considered, including demographics, comorbidities, and time-updated levels of erythropoietin and parenteral iron dosing, medical events, and laboratory and dialysis measures., Results: Compared to Hb 11 to <12 g/dL, subjects with Hb <11 g/dL had increased mortality [adjusted hazard ratios (95% confidence interval) in the 3-month-lagged model = 1.74 (1.24 to 2.43) for <9 g/dL, 1.25 (0.96 to 1.63) for 9 to <10 g/dL, and 1.22 (0.99 to 1.49) for 10 to <11 g/dL categories]. Mortality rates for subjects with Hb 12 to <13 g/dL and > or = 13 g/dL did not differ significantly from those with Hb 11 to <12 g/dL. The relationships between Hb and mortality varied modestly with changes in the time interval between Hb measurement and the time at risk for mortality, but did not vary according to ESRD vintage or health status indicators., Conclusion: Our findings confirm the associations of Hb levels > or =11 g/dL with longer survival among maintenance HD patients, but show no additional survival advantage for patients with Hb levels > or =12 g/dL. Further investigation of the relationships among anemia, treatment of anemia, and survival is warranted.

Nonadherence to immunosuppressive medications may partly explain the worse allograft outcomes among black recipients of renal transplants. In a prospective cohort study of recipients of deceased donor renal transplants, microelectronic cap monitors were placed on bottles of one immunosuppressive medication to (1) measure average daily percentage adherence during the first posttransplantation year and (2) determine the factors associated with adherence. A total of 278 transplant recipients who provided sufficient microelectronic adherence data were grouped into four categories of average daily percentage adherence: 95 to 100% adherence (41.0% of patients), 80 to 95% adherence (32.4%), 50 to 80% adherence (12.9%), and 0 to 50% adherence (13.7%). In the unadjusted ordinal logistic regression model, black race was associated with decreased adherence (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.26 to 0.72; P = 0.001). Cause of renal disease, Powerful Others health locus of control, transplant center, and dosing frequency were also associated with adherence. After adjustment for transplant center and dosing frequency, the association between black race and decreased adherence was substantially attenuated (OR, 0.65; 95% CI, 0.38 to 1.14, P = 0.13). Transplant center (P = 0.003) and increased dosing frequency (OR, 0.43; 95% CI, 0.22 to 0.86, for three or four times per day dosing; OR, 2.35; 95% CI, 1.01 to 5.45, for daily dosing; versus two times per day dosing; P = 0.003) remained independently associated with adherence. Other baseline demographic, socioeconomic, medical, surgical, and psychosocial characteristics were not associated with adherence. The transplant center and dosing frequencies of immunosuppressive medications are associated with adherence and explain a substantial proportion of the race-adherence relationship.

Background: The morbidity and mortality associated with asthma are suspected to be a result, in part, of poor adherence to inhaled corticosteroid regimens. One influence on adherence may be the perception of symptoms. Because symptoms and adherence affect each other over time, a conventional statistical approach for studying these relationships may provide biased results., Objective: To understand the influence of previous asthma symptoms and previous adherence on current symptoms., Methods: A total of 76 adults, mean age 48 years +/- 15 years, with moderate or severe persistent asthma underwent 6 weeks of electronic monitoring of their use of inhaled corticosteroids and completed a daily symptom diary. We estimated the effect of earlier adherence on final symptoms by using marginal structural models, estimated by using a weighted estimation technique., Results: Morning was better than evening adherence, which declined over the observation period. The variability of adherence appeared to increase over the observation period. In addition, earlier adherence predicted current adherence more strongly than earlier symptoms predicted current adherence. There was no overall significant relationship between cumulative adherence and final symptoms., Conclusion: These data indicate that accurately determining past adherence will help identify patients to target to improve their future adherence. These analyses are important for understanding time-varying measures in the clinical setting.

We propose a method for estimating the marginal causal log-odds ratio for binary outcomes under treatment non-compliance in placebo-randomized trials. This estimation method is a marginal alternative to the causal logistic approach by Nagelkerke et al. (2000) that conditions on partially unknown compliance (that is, adherence to treatment) status, and also differs from previous approaches that estimate risk differences or ratios in subgroups defined by compliance status. The marginal causal method proposed in this paper is based on an extension of Robins' G-estimation approach for fitting linear or log-linear structural nested models to a logistic model. Comparing the marginal and conditional causal log-odds ratio estimates provides a way of assessing the magnitude of unmeasured confounding of the treatment effect due to treatment non-adherence. More specifically, we show through simulations that under weak confounding, the conditional and marginal procedures yield similar estimates, whereas under stronger confounding, they behave differently in terms of bias and confidence interval coverage. The parametric structures that represent such confounding are not identifiable. Hence, the proof of consistency of causal estimators and corresponding simulations are based on two different models that fully identify the causal effects being estimated. These models differ in the way that compliance is related to potential outcomes, and thus differ in the way that the causal effect is identified. The simulations also show that the proposed marginal causal estimation approach performs well in terms of bias under the different levels of confounding due to non-adherence and under different causal logistic models. We also provide results from the analyses of two data sets further showing how a comparison of the marginal and conditional estimators can help evaluate the magnitude of confounding due to non-adherence., (Copyright 2003 John Wiley & Sons, Ltd.)

Case-control studies often rely on subjects to report their own screening or exposure information: this information is often obtained from cases after the event of interest has occurred. This is problematic for mortality outcomes, because dead subjects cannot report the desired information. To avoid this problem, Weiss and Lazovich (1996, American Journal of Epidemiology 143, 319-322) proposed obtaining exposure or screening information from potential cases, i.e., subjects diagnosed with disease, at the time of disease diagnosis, and also from a referent series. The design is best viewed as a new scheme for sampling from a cohort. I review estimation of the effects of time-varying screening or exposure in cohort studies, using a new factorization. I then show how this factorization, together with ignorability assumptions, allows valid estimation from these new designs. Even when the sampling fraction of nondiseased subjects is unknown, causal risk ratios are estimable if diagnosis is rare in the cohort. I illustrate and compare conventional and new methods with data from the Health Insurance Plan study.