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Rigorous evaluation of surrogate endpoints is performed in a trial‐level analysis in which the strength of the association between treatment effects on the clinical and surrogate endpoints is quantified across a collection of previously conducted trials. To reduce bias in measures of the performance of the surrogate, the statistical model must account for the sampling error in each trial's estimated treatment effects and their potential correlation. Unfortunately, these within‐study correlations can be difficult to obtain, especially for meta‐analysis of published trial results where individual patient data is not available. As such, these terms are frequently partially or completely missing in the analysis. We show that improper handling of these missing terms can meaningfully alter the perceived quality of the surrogate and we introduce novel strategies to handle the missingness. [ABSTRACT FROM AUTHOR]

Aims: To assess whether the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor canagliflozin affects risk of non‐genital skin and soft tissue infections (SSTIs). Materials and methods: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator‐reported adverse events were assessed by two blinded authors following predetermined criteria for non‐genital SSTIs. Risks of non‐genital SSTIs, overall and within prespecified subgroups, and risk of non‐genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non‐genital SSTIs were assessed using multivariable Cox regression models. Results: Overall, 903 of 14 531 participants (6%) experienced non‐genital SSTIs over a median follow‐up of 26 months. No difference was observed in non‐genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person‐years vs. 23.9 events/1000 person‐years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85‐1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non‐genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94‐1.19 [P = 0.32] and HR 1.18, 95% CI 0.88‐1.60 [P = 0.27], respectively). Baseline factors independently associated with non‐genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. Conclusions: Canagliflozin did not affect risk of non‐genital SSTIs or non‐genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor‐mediated change in skin microenvironment is unlikely to have meaningful clinical consequences. [ABSTRACT FROM AUTHOR]

Objectives: Age is important for prognosis in community‐onset pneumonia, but how it influences admission decisions in the emergency department (ED) is not well characterized. Using clinical data from the electronic health record in a national cohort, we examined pneumonia hospitalization patterns, variation, and relationships with mortality among older versus younger Veterans. Methods: In a retrospective cohort of patients ≥ 18 years presenting to EDs with a diagnosis of pneumonia at 118 VA Medical Centers January 1, 2006, to December 31, 2016, we compared observed, predicted, and residual hospitalization risk for Veterans < 70, 70–79, and ≥ 80 years of age using generalized estimating equations and machine learning models with 71 patient factors. We examined facility variation in residual hospitalization across facilities and explored whether facility differences in hospitalization risk correlated with differences in 30‐day mortality. Results: Among 297,498 encounters, 165,003 (55%) were for Veterans < 70 years, 61,076 (21%) 70–80, and 71,419 (24%) ≥ 80. Hospitalization rates were 52%, 67%, and 76%, respectively. After other patient factors were adjusting for, age 70–79 had an odds ratio (OR) of 1.39 (95% confidence interval [CI] 1.34–1.44) and ≥ 80 had an OR of 2.1 (95% CI 2.0–2.2) compared to age < 70. There was substantial variation in hospitalization across facilities among Veterans < 70 (<35% hospitalization at the lowest decile of facilities vs. > 66% at the highest decile) that was similar but with higher risk for patients 70–79 years (54% vs. 82%) and ≥ 80 years (59% vs. 85%) and remained after accounting for patient factors, with no consistently positive or negative associations with facility‐level 30‐day mortality. Conclusions: Older Veterans with community‐onset pneumonia experience high risk of hospitalization, with widespread facility variation that has no clear relationship to short‐term mortality. [ABSTRACT FROM AUTHOR]

Introduction: Success rates of catheter ablation in persistent atrial fibrillation (AF) remain suboptimal. A better and more targeted ablation strategy is urgently needed to optimize outcomes of AF treatment. We sought to assess the safety and efficacy of targeting atrial fibrosis during ablation of persistent AF patients in improving procedural outcomes. Methods: The DECAAF II trial (ClinicalTrials. gov identifier number NCT02529319) is a prospective, randomized, multicenter trial of patients with persistent AF. Patients with persistent AF undergoing a first‐time ablation procedure were randomized in a 1:1 fashion to receive conventional pulmonary vein isolation (PVI) ablation (Group 1) or PVI + fibrosis‐guided ablation (Group 2). Left atrial fibrosis and ablation induced scarring were defined by late gadolinium enhancement magnetic resonance imaging at baseline and at 3–12 months postablation, respectively. The primary endpoint is the recurrence of atrial arrhythmia postablation, including atrial fibrillation, atrial flutter, or atrial tachycardia after the 90‐day postablation blanking period. Patients were followed for a period of 12–18 months with a smartphone ECG Device (ECG Check Device, Cardiac Designs Inc.). With an anticipated enrollment of 900 patients, this study has an 80% power to detect a 26% reduction in the hazard ratio of the primary endpoint. Results and Conclusion: The DECAAF II trial is the first prospective, randomized, multicenter trial of patients with persistent AF using imaging defined atrial fibrosis as a treatment target. The trial will help define an optimal approach to catheter ablation of persistent AF, further our understanding of influencers of ablation lesion formation, and refine selection criteria for ablation based on atrial myopathy burden. [ABSTRACT FROM AUTHOR]

Background: Atrial fibrillation (AF) significantly reduces health‐related quality of life (HRQoL), previously measured in clinical trials using patient‐reported outcomes (PROs). We examined AF PROs in clinical practice and their association with subsequent clinical management. Methods: The Utah My Evaluation (mEVAL) program collects the Toronto AF Symptom Severity Scale (AFSS) in AF outpatients at the University of Utah. Baseline factors associated with worse AF symptom score (range 0–35, higher is worse) were identified in univariate and multivariable analyses. Secondary outcomes included AF burden and AF healthcare utilization. We also compared subsequent clinical management at 6 months between patients with better versus worse AF HRQoL. Results: Overall, 1338 patients completed the AFSS symptom score, which varied by sex (mean 7.26 for males vs. 10.27 for females; p <.001), age (<65, 9.73; 65–74, 7.66; ≥75, 7.58; p <.001), heart failure (9.39 with HF vs. 7.67 without; p <.001), and prior ablation (7.28 with prior ablation vs. 8.84; p <.001). In multivariable analysis, younger age (mean difference 2.92 for <65 vs. ≥75; p <.001), female sex (mean difference 2.57; p <.001), pulmonary disease (mean difference 1.88; p <.001), and depression (mean difference 2.46; p <.001) were associated with higher scores. At 6‐months, worse baseline symptom score was associated with the use of rhythm control (37.1% vs. 24.5%; p <.001). Similar cofactors and results were associated with increased AF burden and health care utilization scores. Conclusions: AF PROs in clinical practice identify highly‐symptomatic patients, corroborating findings in more controlled, clinical trials. Increased AFSS score correlates with more aggressive clinical management, supporting the utility of disease‐specific PROs guiding clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To describe the progression of sensorineural hearing loss (SNHL) in the better- and poorer-hearing ears in children with asymptomatic congenital cytomegalovirus (CMV) infection with isolated SNHL.Study Design: Longitudinal prospective cohort study.Setting: Tertiary medical center.Subjects and Methods: We analyzed hearing thresholds of the better- and poorer-hearing ears of 16 CMV-infected patients with isolated congenital/early-onset or delayed-onset SNHL identified through hospital-based CMV screening of >30,000 newborns from 1982 to 1992.Results: By 12 months of age, 4 of 7 patients with congenital/early-onset SNHL developed worsening thresholds in the poorer-hearing ear, and 1 had an improvement in the better-hearing ear. By 18 years of age, all 7 patients had worsening thresholds in the poorer-hearing ear and 3 patients had worsening thresholds in the better-hearing ear. Hearing loss first worsened at a mean age of 2 and 6 years in the poorer- and better-hearing ears, respectively. Nine patients were diagnosed with delayed-onset SNHL (mean age of 9 years vs 12 years for the poorer- and better-hearing ears), 6 of whom had worsening thresholds in the poorer-hearing ear and 1 in both ears.Conclusion: In most children with congenital CMV infection and isolated SNHL, the poorer-hearing ear worsened earlier and more precipitously than the better-hearing ear. This study suggests that monitoring individual hearing thresholds in both ears is important for appropriate interventions and future evaluation of efficacy of antiviral treatment. [ABSTRACT FROM AUTHOR]

In March of 2018, the National Kidney Foundation, in collaboration with the US Food and Drug Administration and the European Medicines Agency, sponsored a workshop in which surrogate endpoints other than currently established event-time endpoints for clinical trials in chronic kidney disease (CKD) were presented and discussed. One such endpoint is a slope-based parameter describing the rate of decline in the estimated glomerular filtration rate (eGFR) over time. There are a number of challenges that can complicate such slope-based analyses in CKD trials. These include the possibility of an early but short-term acute treatment effect on the slope, both within-subject and between-subject heteroscedasticity, and informative censoring resulting from patient dropout due to death or onset of end-stage kidney disease. To address these issues, we first consider a class of mixed-effects models for eGFR that are linear in the parameters describing the mean eGFR trajectory but which are intrinsically nonlinear when a power-of-mean variance structure is used to model within-subject heteroscedasticity. We then combine the model for eGFR with a model for time to dropout to form a class of shared parameter models which, under the right specification of shared random effects, can minimize bias due to informative censoring. The models and methods of analysis are described and illustrated using data from two CKD studies one of which was one of 56 studies made available to the workshop analytical team. Lastly, methodology and accompanying software for prospectively determining sample size/power estimates are presented. [ABSTRACT FROM AUTHOR]

ABSTRACT: 12345Responsiveness is the ability to detect change over time and is an important aspect of measures used to detect treatment effects. The purpose of this study was to assess the responsiveness of the HOOS JR, the KOOS JR, and the PROMIS Physical Function (PF) computerized adaptive test (CAT) in a joint reconstruction practice. 983 patients were evaluated for joint conditions between 2014 and 2017 in an orthopaedic clinic and completed the three instruments at baseline and 3 and/or 6‐month follow‐up visits. Average age was 61.03 years (SD = 12.33, Range = 18–90 years) and the majority of the patients were White (n = 875, 89.0%). Three‐month responsiveness was calculated two ways, as between 80 and 100 days and as 90 days and beyond. Six‐month responsiveness was calculated as 170–190 days and as 180 days and beyond. All changes from baseline scores were significant at the 3‐, >3‐, and >6‐month follow‐up (p < 0.05). All three measures showed large effect sizes, ranging from 0.80–1.20 at each time‐point. The standardized response mean was large for each measure and at each time‐point (Range = 1.06–1.53). This study demonstrated the responsiveness of the HOOS JR, KOOS JR, and the PROMIS PF in adult reconstruction patients. The PROMIS PF was consistently the most responsive instrument in this analysis. Clinical significance: The HOOS JR, KOOS JR, and PROMIS PF are useful clinical instruments for assessing treatment change and may be selected as relevant to the specific needs and conditions of the adult joint reconstruction patient population. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1178–1184, 2018. [ABSTRACT FROM AUTHOR]

In patients with chronic kidney disease (CKD), clinical interest often centers on determining treatments and exposures that are causally related to renal progression. Analyses of longitudinal clinical data in this population are often complicated by clinical competing events, such as end-stage renal disease (ESRD) and death, and time-dependent confounding, where patient factors that are predictive of later exposures and outcomes are affected by past exposures. We developed multistate marginal structural models (MS-MSMs) to assess the effect of time-varying systolic blood pressure on disease progression in subjects with CKD. The multistate nature of the model allows us to jointly model disease progression characterized by changes in the estimated glomerular filtration rate (eGFR), the onset of ESRD, and death, and thereby avoid unnatural assumptions of death and ESRD as noninformative censoring events for subsequent changes in eGFR. We model the causal effect of systolic blood pressure on the probability of transitioning into 1 of 6 disease states given the current state. We use inverse probability weights with stabilization to account for potential time-varying confounders, including past eGFR, total protein, serum creatinine, and hemoglobin. We apply the model to data from the Chronic Renal Insufficiency Cohort Study, a multisite observational study of patients with CKD. [ABSTRACT FROM AUTHOR]

Introduction: Oral phosphate binders are the main stay of treatment of hyperphosphatemia. Adherence rates to ferric citrate, a recently approved phosphate binder, are unknown. Methods: We conducted a post-hoc analysis to evaluate whether adherence rates were different for ferric citrate vs. active control in 412 subjects with end stage kidney disease (ESKD) who were randomized to ferric citrate vs. active control (sevelamer carbonate and/or calcium acetate). Adherence was defined as percent of actual number of pills taken to total number of pills prescribed. Findings: There were no significant differences in baseline characteristics including gender, race/ethnicity, and age between the ferric citrate and active control groups. Baseline phosphorus, calcium, and parathyroid hormone levels were similar. Mean (SD) adherence was 81.4% (17.4) and 81.7% (15.9) in the ferric citrate and active control groups, respectively (P = 0.88). Adherence remained similar between both groups after adjusting for gender, race/ethnicity, age, cardiovascular disease (CVD), and diabetic nephropathy (mean [95% CI]: 81.4% [78.2, 84.6] and 81.5% [77.7, 85.2] for ferric citrate and active control, respectively). Gender, race/ethnicity, age, and diagnosis of diabetic nephropathy did not influence adherence to the prescribed phosphate binder. Subjects with CVD had lower adherence rates to phosphate binder; this was significant only in the active control group. Discussion: Adherence rates to the phosphate binder, ferric citrate, were similar to adherence rates to active control. Similar adherence rates to ferric citrate are notable since tolerance to active control was an entry criteria and the study was open label. Gender, race/ethnicity, nor age influenced adherence. [ABSTRACT FROM AUTHOR]

Longitudinal cohort studies often collect both repeated measurements of longitudinal outcomes and times to clinical events whose occurrence precludes further longitudinal measurements. Although joint modeling of the clinical events and the longitudinal data can be used to provide valid statistical inference for target estimands in certain contexts, the application of joint models in medical literature is currently rather restricted because of the complexity of the joint models and the intensive computation involved. We propose a multiple imputation approach to jointly impute missing data of both the longitudinal and clinical event outcomes. With complete imputed datasets, analysts are then able to use simple and transparent statistical methods and standard statistical software to perform various analyses without dealing with the complications of missing data and joint modeling. We show that the proposed multiple imputation approach is flexible and easy to implement in practice. Numerical results are also provided to demonstrate its performance. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis Identify hospital costs for same-day pediatric adenotonsillectomy (T&A) surgery, and evaluate surgeon, hospital, and patient factors influencing variation in costs, and compare relationship of costs to complications for T&A. Study Design Observational retrospective cohort study. Methods A multihospital network's standardized activity-based accounting system was used to determine hospital costs per T&A from 1998 to 2012. Children 1 to 18 years old who underwent same-day T&A surgery were included. Subjects with additional procedures were excluded. Mixed effects analyses were performed to identify variation in mean costs due to surgeon, hospital, and patient factors. Surgeons' mean cost/case was related to subsequent complications, defined as any unplanned visit within 21 days in the healthcare system. Results The study cohort included 26,626 T&As performed by 66 surgeons at 18 hospitals. Mean cost per T&A was $1,355 ± $505. Mixed effects analysis using patient factors as fixed effects and surgeon and hospital as a random effect identified significant variation in mean costs per surgeon, with 95% of surgeons having a mean cost/case between 67% and 150% of the overall mean (range, $874-$2,232/case). Similar variability was found among hospitals, with 95% of the facilities having mean costs between 64% to 156% of the mean (range, $1,029-$2,385/case). Severity of illness and several other patient factors exhibited small but statistically significant associations with cost. Surgeons' mean cost/case was moderately associated with an increased complication rate. Conclusions Significant variation in same-day pediatric T&A surgery costs exists among different surgeons and hospitals within a multihospital network. Reducing variation in costs while maintaining outcomes may improve healthcare value and eliminate waste. Level of Evidence 4. Laryngoscope, 125:1215-1220, 2015 [ABSTRACT FROM AUTHOR]

Aim Low serum bicarbonate is a strong mortality risk factor in people with low estimated glomerular filtration rate ( eGFR). It may also raise mortality risk in people with normal eGFR. This study investigated whether higher net endogenous acid production ( NEAP), an estimate of net dietary acid intake and a risk factor for chronic kidney disease ( CKD) progression, associates with higher mortality in people with and without low eGFR. Methods NEAP was calculated among adult participants in the Third National Health and Nutrition Examination Survey as −10.2 + 54.5 x (protein intake in grams per day/potassium intake in milliequivalent per day). Cox models were performed in the (i) total population and (ii) low eGFR and (iii) normal eGFR subgroups using the lowest NEAP quartile as the reference. Results Sixteen thousand nine hundred six participants were included in the analysis. The mortality hazard ratios (95% confidence interval) for the highest NEAP quartile (72-145 mEq/day) were: (i) 0.75 (0.62-0.90) in the total population; (ii) 0.77 (0.51-1.17) in the low eGFR subgroup; and (iii) 0.75 (0.61-0.93) in the normal eGFR subgroup after adjusting for demographics, serum bicarbonate, eGFR, albuminuria and comorbidities. The mortality hazard ratios in the second and third NEAP quartiles were similar to the lowest (reference) NEAP quartile in the total population and low and normal eGFR subgroups. Conclusions Higher NEAP is not associated with higher mortality in people with low or normal eGFR. Future studies should consider the effect of modifying dietary acid and alkali intake on mortality and CKD progression in people with reduced eGFR. [ABSTRACT FROM AUTHOR]

Aim The prevalence of metabolic acidosis increases as glomerular filtration rate falls. However, most patients with stage 4 chronic kidney disease have normal serum bicarbonate concentration while some with stage 3 chronic kidney disease have low serum bicarbonate, suggesting that other factors contribute to generation of acidosis. The purpose of this study is to identify risk factors, other than reduced glomerular filtration rate, for reduced serum bicarbonate in chronic kidney disease. Methods This is a cross-sectional analysis of baseline data from the Chronic Renal Insufficiency Cohort Study. Multivariable logistic and linear regression models were used to relate predictor variables to the odds of low serum bicarbonate (<22 mM) compared with normal serum bicarbonate (22-30 mM) and the coefficients of Δ serum bicarbonate concentration. Results The prevalence of low serum bicarbonate at baseline was 17.3%. Lower estimated glomerular filtration rate had the strongest relationship with low serum bicarbonate. Factors associated with higher odds of low serum bicarbonate, independent of estimated glomerular filtration rate, were urinary albumin/creatinine ≥10 mg/g, smoking, anaemia, hyperkalaemia, non-diuretic use and higher serum albumin. These and younger age, higher waist circumference, and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers associated with negative Δ serum bicarbonate in linear regression models. Conclusions Several factors not typically considered to associate with reduced serum bicarbonate in chronic kidney disease were identified including albuminuria ≥10 mg/g, anaemia, smoking, higher serum albumin, higher waist circumference, and use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Future studies should explore the longitudinal effect of these factors on serum bicarbonate concentration. [ABSTRACT FROM AUTHOR]

When running the SAS program "SIM Supplement - SAS code for MDRD-B Example.sas", an error will occur whenever one uses the FIXED KNOT= option of the SAS macro %GetKnot. In the SOFTWARE CODE AND DATA ACCESSIBILITY statement at the end of our article "Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease", we provide access to two SAS programs used in the article through the repository Figshare. We recently became aware of two errors in our SAS code, one error in the SAS program file "SIM Supplement - SAS code for MDRD-B Example.sas" and one in the SAS program file "SIM Supplement - SAS MACRO GFR Slope Power.sas" both of which are located in the Figshare repository which can be accessed via the link at the end of our article. [Extracted from the article]

In 2004, the Pennsylvania Fish and Boat Commission implemented catch-and-release (CR) regulations on headwater stream systems to determine if eliminating angler harvest would result in an increase in the number of adult (≥100 mm) or large (≥175 mm) Brook TroutSalvelinus fontinalis. Under the CR regulations, angling was permitted on a year-round basis, no Brook Trout could be harvested at any time, and there were no tackle restrictions. A before-after–control-impact design was used to evaluate the experimental regulations. Brook Trout populations were monitored in 16 treatment (CR regulations) and 7 control streams (statewide regulations) using backpack electrofishing gear periodically for up to 15 years (from 1990 to 2003 or 2004) before the implementation of the CR regulations and over a 7–8-year period (from 2004 or 2005 to 2011) after implementation. We used Poisson mixed models to evaluate whether electrofishing catch per effort (CPE; catch/100 m2) of adult (≥100 mm) or large (≥175 mm) Brook Trout increased in treatment streams as a result of implementing CR regulations. Brook Trout CPE varied among sites and among years, and there was no significant effect (increase or decrease) of CR regulations on the CPE of adult or large Brook Trout. Results of our evaluation suggest that CR regulations were not effective at improving the CPE of adult or large Brook Trout in Pennsylvania streams. Low angler use, high voluntary catch and release, and slow growth rates in infertile headwater streams are likely the primary reasons for the lack of response. Received June 14, 2013; accepted August 28, 2013 [ABSTRACT FROM AUTHOR]

This paper proposes a nonparametric procedure to describe the progression of longitudinal cohorts over time from a population averaged perspective, leading to multistate probability curves with the states defined jointly by survival and longitudinal outcomes measured with error. To account for the challenges of informative dropout and nonlinear shapes of the longitudinal trajectories, we apply a bias corrected penalized spline regression to estimate the unobserved longitudinal trajectory for each subject. We then estimate the multistate probability curves on the basis of the survival data and the estimated longitudinal trajectories. We further use simulation-extrapolation method to reduce the estimation bias caused by the randomness of the estimated trajectories. We develop a bootstrap test to compare multistate probability curves between groups. We present theoretical justification of the estimation procedure along with a simulation study to demonstrate finite sample performance. We illustrate the procedure by data from the African American Study of Kidney Disease and Hypertension, and it can be widely applied in longitudinal studies. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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When evaluating clinical characteristics and outcomes in patients on hemodialysis, the prevalence and severity of comorbidity may change over time. Knowing whether updated assessments of comorbidity enhance predictive power will assist the design of future studies. We conducted a secondary data analysis of 1846 prevalent hemodialysis patients from 15 US clinical centers enrolled in the HEMO study. Our primary explanatory variable was the Index of Coexistent Diseases score, which aggregates comorbidities, as a time-constant and time-varying covariate. Our outcomes of interest were all-cause mortality, time to first hospitalization, and total hospitalizations. We used Cox proportional hazards regression. Accounting for an updated comorbidity assessment over time yielded a more robust association with mortality than accounting for baseline comorbidity alone. The variation explained by time-varying comorbidity assessments on time to death was greater than age, baseline serum albumin, diabetes, or any other covariates. There was a less pronounced advantage of updated comorbidity assessments on determining time to hospitalization. Updated assessments of comorbidity significantly strengthen the ability to predict death in patients on hemodialysis. Future studies in dialysis should invest the necessary resources to include repeated assessments of comorbidity. [ABSTRACT FROM AUTHOR]

Classic urea modeling assumes that both urea generation rate (G) and residual renal urea clearance (Kru) are constant throughout the week, but this may not be true. Reductions in intradialysis G could be caused by lower plasma amino acid levels due to predialysis/intradialysis fasting and also to losses of amino acids into the dialysate. Intradialytic reductions in Kru could be due to lower intravascular volume, blood pressure, or osmotic load. To determine the possible effects of reduced G or Kru during dialysis on the calculation of the volume of distribution (V) and Kt/Vurea, we modeled 3 and 6/week nocturnal, 6/week short daily, and 3/week conventional hemodialysis. A modified 2-pool mathematical model of urea mass balance with a constant time-averaged G was used, but the model was altered to allow adjustment of the ratio of dialytic/interdialytic G ( Gd/ Gid) and dialytic/total Kru (Krud/Kru) to vary from 1.0 down to near zero. In patients dialyzed six times per week for 400 minutes per session, when Gd/ Gid was decreased from 1.0 to 0.05, the predicted urea reduction ratio (URR) increased from 68.9% to 80.2%. To achieve an increased URR of this magnitude under conditions of constant G ( Gd/ Gid = 1.0) required a decrease in modeled urea volume (V) of 36%. At Gd/ Gid ratios of 0.8 or 0.6 (corresponding to 20% or 40% reductions in intradialysis G), the modeled URR was increased to 71.0% or 73.3%, causing a 7% or 15% factitious decrease in V. The error was intermediate for the 3/week nocturnal schedule, and was much less pronounced for the 6/week daily and 3/week conventional treatments. Reductions in intradialytic Kru had the opposite effect, lowering the predicted URR and increasing the apparent V, but here the errors were of much lesser amplitude. The results suggest that, particularly for nocturnal dialysis, the standard “constant G” urea kinetic model may need to be modified. [ABSTRACT FROM AUTHOR]

The concordance between predicted and observed outcomes, referred to as the C index or C statistic, is frequently used to quantify the discriminatory ability of a prognostic model. It also commonly serves as a basis for distinguishing predictive strength between different models. Two alternative formulations of the C index are widely used, one completely excluding ties from the computation ( Ctied,out) and the other including ties ( Ctied,in). However, there has been little research concerning the effects of ties on these two measures. In this paper we characterize changes in the performance of Ctied,in and Ctied,out for progressively less coarse (or more coarse) partitions of the data. Our theoretical and simulation results show that both measures can be heavily dependent on the number of tied pairs and their results can be substantially divergent. We examine potential ambiguities that can occur when the two measures diverge. In the presence of a substantial proportion of tied pairs, we recommend that both C indices be computed as lower and upper bounds, and that, when feasible, the C indices should be computed with respect to partitions corresponding to the same percentiles for the models being compared. When it is desired to estimate the overall concordance, the average value of the two C indices might also be considered. We use the data from the Hemodialysis Clinical Trial to illustrate our evaluation and methods. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To assess the extent to which persons aged 70 and older undergoing hemodialysis (HD) had greater changes in health-related quality of life (HRQOL) over 3 years than younger patients undergoing HD. DESIGN: Longitudinal. SETTING: The Hemodialysis Study (HEMO Study) was a randomized, clinical trial of the effects of HD dose and membrane flux on mortality and morbidity in patients undergoing chronic dialysis. PARTICIPANTS: Secondary analysis of the HEMO Study. MEASUREMENTS: Participants completed the Index of Well-Being (IWB) and the Kidney Disease Quality of Life—Long Form (KDQOL-LF), which also includes the Medical Outcomes Study 36-item Short Form Questionnaire (SF-36) annually. Changes in subjects those aged 70 and older were compared with changes in subjects aged 55 to 69 and 18 to 54. RESULTS: At baseline, 1,813 (98%) of HEMO participants completed HRQOL surveys. Their mean age was 58, 56% were female, 64% were black, and mean duration of dialysis was 3.8 years. In subjects with HRQOL data at the first three annual assessments, there were no substantial mean declines in the SF-36 Physical or Mental Component Summary scales over 3 years. In models incorporating effects of attrition, the differences in average change over 3 years between patients undergoing HD aged 70 and older and the younger cohorts were small in magnitude. There were high rates of adverse HRQOL events in all age groups and significantly higher composite event rates of death or clinically significant decline in HRQOL over 3 years was found in subjects aged 70 and older. CONCLUSION: Although HRQOL was impaired in the population undergoing HD, HRQOL scores at baseline reflect a better-preserved multidimensional quality of life in respondents in the HEMO Study aged 70 and older than in younger patients undergoing HD. There was no substantial relationship between age and average decline in HRQOL score over 3 years in participants in the HEMO Study. [ABSTRACT FROM AUTHOR]

Dialysis is measured as Kt/ V, which scales the dose ( Kt) to body water content ( V). Scaling dialysis dose to body surface area ( Sdub) has been advocated, but the implications of such rescaling have not been examined. We developed a method of rescaling measured Kt/ V to Sdub and studied the effect of such alternative scaling on the minimum adequacy values that might then be applied in male and female patients of varying body size. We examined anthropometric estimates of V and S (Watson vs. Dubois estimates) in 1765 patients enrolled in the HEMO study after excluding patients with amputations. An S-normalized target std Kt/ V was defined, and an adequacy ratio ( R) was computed for each patient as R = D/ N where D = delivered std Kt/ V (calculated using the Gotch–Leypoldt equation for std Kt/ V) and N = the S-normalized minimum target value. In the HEMO data set, we determined the extent to which baseline (prerandomization) std Kt/ V values would have exceeded such an S-based minimum target std Kt/ V. The median Vwat: Sdub ratios were significantly higher in men (21.34) than in women (18.50). The average of these (20) was used to normalize the current suggested minimally adequate value (std Kt/ V ≥ 2.0/week) to the S-normalized target value (std Kt/ S ≥ 40 L/ M2), assuming that average modeled V = average anthropometric V. To achieve this S-normalized target, the required single-pool (sp) Kt/ V was always higher in women than in men at any level of body size. For small patients ( Vwat = 25 L), required std Kt/ V values were 2.05 and 2.21/week for men and women, respectively, corresponding to sp Kt/ V values of 1.31 and 1.52/session. On the other hand, large ( Vwat = 50 L) male patients would need sp Kt/ V values of only 1.0/session. Prerandomization baseline dialysis sessions in the HEMO study were found to meet such a new S-based standard in almost all (766/773) men and in 885/992 women. An analysis of scaling dose to anthropometrically estimated liver size ( L) showed similar gender ratios for Vwat: L and Vwat: Sdub, providing a potential physiologic explanation underpinning S-based scaling. S-based scaling of the dialysis dose would require considerably higher doses in small patients and in women, and would allow somewhat lower doses in larger male patients. Current dialysis practice would largely meet such an S-based adequacy standard if the dose were normalized to a Vwat: Sdub ratio of 20. [ABSTRACT FROM AUTHOR]

Longitudinal studies often gather joint information on time to some event (survival analysis, time to dropout) and serial outcome measures (repeated measures, growth curves). Depending on the purpose of the study, one may wish to estimate and compare serial trends over time while accounting for possibly non-ignorable dropout or one may wish to investigate any associations that may exist between the event time of interest and various longitudinal trends. In this paper, we consider a class of random-effects models known as shared parameter models that are particularly useful for jointly analysing such data; namely repeated measurements and event time data. Specific attention will be given to the longitudinal setting where the primary goal is to estimate and compare serial trends over time while adjusting for possible informative censoring due to patient dropout. Parametric and semi-parametric survival models for event times together with generalized linear or non-linear mixed-effects models for repeated measurements are proposed for jointly modelling serial outcome measures and event times. Methods of estimation are based on a generalized non-linear mixed-effects model that may be easily implemented using existing software. This approach allows for flexible modelling of both the distribution of event times and of the relationship of the longitudinal response variable to the event time of interest. The model and methods are illustrated using data from a multi-centre study of the effects of diet and blood pressure control on progression of renal disease, the modification of diet in renal disease study. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Discusses mathematical coupling and the association between Kt/V and PCR[sub n] as measurements of dialysis dose and of protein nitrogen appearance, respectively. Calculation of Kt/V and PCR[sub n]; Measurement of dialysis dose directly related to dialysis prescription but not influenced by protein catabolism; Estimation of protein nitrogen appearance distinct from the dialysis dose.

A neonatal examination for fetal alcohol syndrome (FAS) should promote the guidance of parents, the planning of remediation for affected children, and the collection of prevalence data. A blinded examination of FAS characteristics conducted as part of a large prospective study of disadvantaged alcohol-exposed infants identified eight neonates who met the published criteria for FAS. These children were followed through the preschool years with a blinded assessment protocol. Seven of these children were found to have no impairment in cognitive and language development, when compared with their peers, and to be of average size. The one child who was mentally and growth retarded at follow-up who had been diagnosed as FAS might not have been diagnosed FAS using clinical criteria (as opposed to blinded research criteria), because his mother provided in-pregnancy reports of only low alcohol intake; she later acknowledged drinking an average of over 21 drinks/week during the pregnancy. The findings are positive in that they provide hope for children who present FAS at birth, although concern with adverse outcomes is certainly not dispelled. In particular, the possibility of later-emerging impairment in more complex tasks is not ruled out. [ABSTRACT FROM AUTHOR]

This report examines the effects of fetal alcohol exposure on size and growth in an urban cohort followed prospectively through early childhood. Indices of prenatal drinking were related to measurements of weight, stature (length), and head circumference obtained at birth and during five subsequent in-home assessments. Small but statistically Significant relationships were detected between short-term recall estimates of drinking during pregnancy and weight and length at birth. The strength of these relationships diminished during the preschool assessments. However, estimates of catch-up growth associated with alcohol exposure were not statistically significant. With the exception of a single case with a profile of signs characteristic of fetal alcohol syndrome, an adverse effect of prenatal alcohol exposure on head circumference was not indicated. [ABSTRACT FROM AUTHOR]

The effects of fetal alcohol exposure on language and speech acquisition were investigated in a cohort of socioeconomically disadvantaged urban children. Language development was assessed by instruments derived from the Expressive and Receptive Scales of the Sequenced Inventory of Communication Development (SICD) at 1, 2, and 3 years, and by indices constructed from a taped speech sample at age 2 years. Three indices of maternal drinking were supplemented with birth weight and a tally of craniofacial anomalies as early indicators of fetal alcohol damage. No statistically significant relationships were found between the alcohol and language indices after statistical control for confounding variables. The anomalies tally was marginally related to reduced language scores. The statistical significance of this relationship, depended, however, on a single child with the characteristics of fetal alcohol syndrome. The pattern of results suggested that the anomalies tally, and to a lesser extent birth weight, are more sensitive indicators of fetal alcohol exposure than subsequent language development. [ABSTRACT FROM AUTHOR]

Background The sodium-glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events. Methods and Results The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m 2 , over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63-0.86]; P <0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59-0.86]; P <0.001). The absolute risk difference per 1000 patients treated over 2.5 years was -44 (95% CI, -67 to -21) first cardiovascular events and -73 (95% CI, -114 to -33) total events. Conclusions Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events. Registration Information URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02065791.