Biased estimation with shared parameter models in the presence of competing dropout mechanisms.

Recently, Thomadakis et al. quantified potential sources of bias that can occur when shared parameter (SP) models are used to jointly model longitudinal trends of a biomarker over time (e.g., a slope) and time-to-dropout in an effort to address concerns over possible informative censoring. Although SP models induce no bias under a missingness completely at random dropout mechanism, the authors demonstrate that bias can occur under a missingness at random (MAR) dropout mechanism wherein dropout depends on the observed biomarker data. To address this, the authors propose including the most recent observed marker value within the hazard function for the time-to-dropout portion of an SP model. They demonstrate via a limited simulation that the proposed model minimizes bias under a specific MAR dropout mechanism and a specific missingness not-at-random dropout mechanism. In the present article, we compare and contrast their work with that of previous authors by illustrating via simulation and an example the degree of bias or lack thereof that can occur when applying SP models, particularly, in the presence of competing dropout mechanisms. We propose the use of a competing risk SP model as a means to minimize bias whenever competing dropout mechanisms are suspected assuming the competing mechanisms result from distinct observable causes of dropout.

Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression.

BACKGROUND: Acute changes in GFR can occur after initiation of interventions targeting progression of CKD. These acute changes complicate the interpretation of long-term treatment effects. METHODS: To assess the magnitude and consistency of acute effects in randomized clinical trials and explore factors that might affect them, we performed a meta-analysis of 53 randomized clinical trials for CKD progression, enrolling 56,413 participants with at least one estimated GFR measurement by 6 months after randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable metaregression to assess the effect of intervention type, disease state, baseline GFR, and albuminuria on the magnitude of acute effects. RESULTS: The mean acute effect across all studies was -0.21 ml/min per 1.73 m2 (95% confidence interval, -0.63 to 0.22) over 3 months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 ml/min per 1.73 m2). We observed negative average acute effects in renin angiotensin system blockade, BP lowering, and sodium-glucose cotransporter 2 inhibitor trials, and positive acute effects in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with a higher mean baseline GFR. CONCLUSION: The magnitude and consistency of acute GFR effects vary across different interventions, and are larger at higher baseline GFR. Understanding the nature and magnitude of acute effects can help inform the optimal design of randomized clinical trials evaluating disease progression in CKD.

Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency.

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

Mixed-effects models for slope-based endpoints in clinical trials of chronic kidney disease.

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.

GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Meta-Analysis of Treatment Effects of Randomized Controlled Trials.

BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point. RESULTS: Across all studies, the treatment effect on 3-year total GFR slope (median R2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. CONCLUSIONS: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation.

BACKGROUND: Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up. METHODS: We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up. RESULTS: In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions. CONCLUSIONS: Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.

Association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder: US-based retrospective cohort study.

OBJECTIVE: To estimate the association between cumulative anticholinergic burden and falls and fractures in patients with overactive bladder (OAB). DESIGN: A retrospective claims-based study (2007-2015) of patients with OAB; outcomes from a subset were contrasted to a non-OAB comparison. SETTING: United States, commercially and Medicare-insured population. PARTICIPANTS: 154 432 adults with OAB and 86 966 adults without OAB, mean age of 56 years, and 67.9% women. MAIN OUTCOME MEASURES: Cumulative anticholinergic burden, a unitless value representing exposure over time, was estimated over the 12 months pre-index ('at baseline') and every 6 months post index. Burden was categorised as no burden (0), low burden (1-89), medium burden (90-499) or high burden (500+). Unadjusted rates of falls or fractures were estimated, and the increased risk associated with anticholinergic burden (measured at the closest 6-month interval prior to a fall or fracture) was assessed using a Cox proportional hazards model and a marginal structural model. RESULTS: Median (IQR) baseline anticholinergic burden was 30 (0.0-314.0) and higher among older (≥65 years, 183 [3.0-713.0]) versus younger (<65 years, 13 [0.0-200.0]) adults. The unadjusted rate of falls or fractures over the period was 5.0 per 100 patient-years, ranging from 3.1 (95% CI 3.0-3.2) for those with no burden, to 7.4 (95% CI 7.1-7.6) for those with high burden at baseline. The adjusted risk of falls and fractures was greater with higher anticholinergic burden in the previous 6 months, with an HR of 1.2 (95% CI 1.2 to 1.3) for low burden versus no burden, to 1.4 (95% CI 1.3 to 1.4) for high versus no burden. Estimates from marginal structural models adjusting for time-varying covariates were lower but remained significantly higher with a higher anticholinergic burden. Rates of falls and fractures were approximately 40% higher among those with OAB (vs those without). CONCLUSION: Higher levels of anticholinergic burden are associated with higher rates of falls and fractures, highlighting the importance of considering anticholinergic burden when treating patients with OAB.

Calculating Standard Kt/V during Hemodialysis Based on Urea Mass Removed.

BACKGROUND/AIMS: We derived a novel equation for calculating weekly urea standard Kt/V (stdKt/V) during hemodialysis (HD) based on urea mass removed, comparable to the approach during peritoneal dialysis. METHODS: Theoretical consideration of urea mass balance during HD led to the following equation for stdKt/V, namely, stdKt/V = N × (URR + UFV/V), where N is the number of treatments per week, URR is urea reduction ratio per treatment, UFV is ultrafiltration volume per treatment, and V is postdialysis urea distribution volume. URR required corrections for postdialysis rebound and intradialytic urea generation. We compared the accuracy of this approach with previous equations for stdKt/V by numerical simulations using a 2-compartment model of urea kinetics for thrice-weekly and more frequent HD prescriptions. RESULTS: The proposed equation based on urea mass removed predicted values of stdKt/V that are equivalent to those calculated by previous equations for stdKt/V. CONCLUSION: This work provides a novel approach for calculating stdKt/V during HD and strengthens the theoretical understanding of stdKt/V.

Survival of propensity matched incident peritoneal and hemodialysis patients in a United States health care system.

We sought to compare survival among incident peritoneal dialysis (PD) patients to matched hemodialysis (HD) patients who received pre-dialysis care, including permanent dialysis access placement. Patients starting PD were propensity matched to those starting HD. HD patients who used a central venous catheter during the first 90 days of dialysis were excluded. Stratified Cox proportional hazards models were used to compare patient survival using both intent-to-treat and as-treated analyses. In the intent-to-treat analysis, patients were followed from the date of first dialysis until death and censored at the earliest of the following: renal transplantation, death, renal recovery, loss to follow-up or study end. In the as-treated analysis, patients were also censored at the time of modality change. A total of 1003 matched pairs were obtained from 11,301 incident patients (10,298 HD and 1003 PD). The cumulative hazard ratio for death at one year was 2.38 (95% CI 1.68-3.40) and 2.10 (1.50-2.94) for HD relative to PD patients in the as-treated and intent-to-treat analyses, respectively. The cumulative risk of death, as estimated by the cumulative hazard ratio, favored PD for almost up to 3 years of follow-up in the as-treated analysis and nearly 2 years of follow-up in the intent-to-treat analysis with no differences thereafter. The higher adjusted rate of death observed for HD patients cannot be attributed to initial use of central venous catheters or lack of pre-dialysis care.

PSA enzymatic activity: a new biomarker for assessing prostate cancer aggressiveness.

BACKGROUND: With the advent of widespread prostate-specific antigen (PSA) testing in recent decades, prostate cancer (PCa) has emerged as the most frequently diagnosed non-skin cancer among men in the U.S. and Europe. Greater screening rates coupled with improved detection methods have caused a controversial upsurge in the number of men undergoing prostate biopsy and subsequent treatment. However, current diagnostic techniques generally suffer from limited ability to identify which seemingly indolent cancers are biologically aggressive. METHODS: We collected prostatic fluid from 778 post-radical prostatectomy specimens and randomly selected samples from both the clinically confirmed aggressive (n = 50) and non-aggressive (n = 50) prostate cancer populations. We measured the level of proteolytic enzyme activity of PSA (aPSA) in each sample and used receiver operating characteristic (ROC) analysis to correlate aPSA levels with prostate cancer aggressiveness. RESULTS: We found aPSA in prostatic fluid to be inversely proportional to disease stage, such that patients with the most aggressive PCa have on average significantly reduced aPSA compared to those with less aggressive disease. Significantly, our results suggest that many (22% in our study population) of the diagnosed patients with non-aggressive PCa could have averted or delayed radical prostatectomy. CONCLUSIONS: Given the high level of debate surrounding PSA screening effectiveness [3-5] and the recent U.S. Preventative Services Task Force recommendation to discontinue PSA screening [6], our results provide renewed hope that a clinical monitoring tool may emerge that truly refines PCa treatment decision-making.

Hemodialysis and peritoneal dialysis are associated with similar outcomes for end-stage renal disease treatment in Canada.

BACKGROUND: There were 35 265 patients receiving renal replacement therapy in Canada at the end of 2007 with 11.0% of patients on peritoneal dialysis (PD) and 48.9% on hemodialysis (HD) and a remaining 40.1% living with a functioning kidney transplant. There are no contemporary studies examining PD survival relative to HD in Canada. The objective was to compare survival outcomes for incident patients starting on PD as compared to HD in Canada. METHODS: Using data from the Canadian Organ Replacement Register, the Cox proportional hazards (PH) model was employed to study survival outcomes for patients initiating PD as compared to HD in Canada from 1991 to 2004 with follow-up to 31 December 2007. Comparisons of outcomes were made between three successive calendar periods: 1991-95, 1996-2000 and 2001-04 with the relative risk of death of incident patients calculated using an intent-to-treat (ITT) analysis with proportional and non-PH models using a piecewise exponential survival model to compare adjusted mortality rates. RESULTS: In the ITT analysis, overall survival for the entire study period favored PD in the first 18 months and HD after 36 months. However, for the 2001-04 cohort, survival favored PD for the first 2 years and thereafter PD and HD were similar. Among female patients > 65 years with diabetes, PD had a 27% higher mortality rate. CONCLUSIONS: Overall, HD and PD are associated with similar outcomes for end-stage renal disease treatment in Canada.

Hemodialysis vascular access modifies the association between dialysis modality and survival.

Several comparisons of peritoneal dialysis (PD) and hemodialysis (HD) in incident patients with ESRD demonstrate superior survival in PD-treated patients within the first 1 to 2 years. These survival differences may be due to higher HD-related mortality as a result of high rates of incident central venous catheter (CVC) use or due to an initial survival advantage conferred by PD. We compared the survival of incident PD patients with those who initiated HD with a CVC (HD-CVC) or with a functional arteriovenous fistula or arteriovenous graft (HD-AVF/AVG). We used multivariable piece-wise exponential nonproportional and proportional hazards models to evaluate early (1 year) mortality as well as overall mortality during the period of observation using an intention-to-treat approach. We identified 40,526 incident adult dialysis patients from the Canadian Organ Replacement Register (2001 to 2008). Compared with the 7412 PD patients, 1-year mortality was similar for the 6663 HD-AVF/AVG patients but was 80% higher for the 24,437 HD-CVC patients (adjusted HR, 1.8; 95% confidence intervals [CI], 1.6 to 1.9). During the entire period of follow-up, HD-AVF/AVG patients had a lower risk for death, and HD-CVC patients had a higher risk for death compared with patients on PD. In conclusion, the use of CVCs in incident HD patients largely accounts for the early survival benefit seen with PD.

What is the true number needed to screen and treat to save a life with prostate-specific antigen testing?

PURPOSE: The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction with prostate-specific antigen (PSA) screening. However, they estimated a number needed to screen (NNS) of 1,410 and a number needed to treat (NNT) of 48 to prevent one prostate cancer death at 9 years. Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, in a survival study setting such as the ERSPC, NNS and NNT are time specific, and reporting values at one time point may lead to misinterpretation of results. Our objective was to re-examine the effect of varying follow-up times on NNS and NNT using data extrapolated from the ERSPC report. MATERIALS AND METHODS: On the basis of published ERSPC data, we modeled the cumulative hazard function using a piecewise exponential model, assuming a constant hazard of 0.0002 for the screening and control groups for years 1 to 7 of the trial and different constant rates of 0.00062 and 0.00102 for the screening and control groups, respectively, for years 8 to 12. Annualized cancer detection and drop-out rates were also approximated based on the observed number of individuals at risk in published ERSPC data. RESULTS: According to our model, the NNS and NNT at 9 years were 1,254 and 43, respectively. Subsequently, NNS decreased from 837 at year 10 to 503 at year 12, and NNT decreased from 29 to 18. CONCLUSION: Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls. With additional follow-up in the ERSPC, if the mortality difference continues to grow, the NNT to save a life with PSA screening will decrease.

Assessing creatinine clearance from modification of diet in renal disease study equations in the ADEMEX cohort: limitations and potential applications.

BACKGROUND AND OBJECTIVES: Twenty-four-hour urine and dialysate collections provide accepted means to assess adequacy in peritoneal dialysis (PD). Recent publications suggest that creatinine clearance (CrCl) estimated from the Modification of Diet in Renal Disease (MDRD) equations (eCrCl) accurately approximates measured CrCl (mCrCl) derived from 24-hour collections of urine and dialysate and might serve as an alternative means to assess small-solute clearance and adequacy in PD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Post hoc analysis of data from patients enrolled in ADEMEX was used to assess agreement between mCrCl and eCrCl derived by four- and six-variable MDRD equations (4V-MDRDE and 6V-MDRDE, respectively). Additionally, associations among mCrCl, eCrCl, and survival were determined. RESULTS: Acceptable precision was observed between mCrCl and 4V-MDRDE-eCrCl and 6V-MDRDE-eCrCl for the entire cohort. Precision was markedly diminished when analysis was limited to functionally anuric patients with mCrCl < 12 ml/min per 1.73 m². Although there was no association between survival and mCrCl, for every 1-ml/min per 1.73 m² increase in 4V- and 6V-MDRDE-eCrCl, there was a 6% and 4% increase in risk of death, respectively. There was a negative association between MDRDE-eCrCl and creatinine appearance rates, suggesting MDRDE-eCrCl is significantly confounded by individual differences in muscle mass. CONCLUSIONS: MDRDE-eCrCl provides demographically comparable values to 24-hour urine and dialysate collections across the ADEMEX cohort. However, MDRDEs should not be used to assess small-solute removal or adequacy in individual PD patients or to predict outcome in any cohort of patients over narrow ranges of limited clearance.

Similar outcomes with hemodialysis and peritoneal dialysis in patients with end-stage renal disease.

BACKGROUND: The annual payer costs for patients treated with peritoneal dialysis (PD) are lower than with hemodialysis (HD), but in 2007, only 7% of dialysis patients in the United States were treated with PD. Since 1996, there has been no change in the first-year mortality of HD patients, but both short- and long-term outcomes of PD patients have improved. METHODS: Data from the US Renal Data System were examined for secular trends in survival among patients treated with HD and PD on day 90 of end-stage renal disease (HD, 620 020 patients; PD, 64 406 patients) in three 3-year cohorts (1996-1998, 1999-2001, and 2002-2004) for up to 5 years of follow-up using a nonproportional hazards marginal structural model with inverse probability of treatment and censoring weighting. RESULTS: There was a progressive attenuation in the higher risk for death seen in patients treated with PD in earlier cohorts; for the 2002-2004 cohort, there was no significant difference in the risk of death for HD and PD patients through 5 years of follow-up. The median life expectancy of HD and PD patients was 38.4 and 36.6 months, respectively. Analyses in 8 subgroups based on age (<65 and ≥65 years), diabetic status, and baseline comorbidity (none and ≥1) showed greater improvement in survival among patients treated with PD relative to HD at all follow-up periods. CONCLUSION: In the most recent cohorts, patients who began treatment with HD or PD have similar outcomes.

Changes in free water fraction and aquaporin function with dwell time during continuous ambulatory peritoneal dialysis.

Diffusive (K(BD), A0/Δx(t)) transport parameters and sieving coefficients (S) for small solutes and free water fraction (FWF), that is, the fraction of total water flow that is transported through aquaporins, were assessed as functions of dwell time t for 35 continuous ambulatory peritoneal dialysis patients using glucose 3.86% dialysis fluid.The individual values of the unrestricted pore area over diffusion distance, A0/Δx(t), were estimated using the mixed effects nonlinear regression and applied for evaluation of S(t) for sodium and FWF(t). FWF decreased on average from the initial 51% of the total transcapillary water flow to 36% at 120 min, whereas the small pore water fraction and sodium sieving coefficient increased. Our results were consistent with the three-pore model if the contribution of the transcellular pores (α(TP)) at the beginning of dwell study was doubled and later decreased to the standard value of 0.02.We conclude that transport characteristics of fluid and small solutes should be considered as time-dependent variables during the peritoneal dialysis.