Meta-analysis for individual participant data with a continuous exposure: A case study

OBJECTIVE: Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. STUDY DESIGN AND SETTING: A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. RESULTS: The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. CONCLUSION: These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment

Carvedilol and cardiac biomarkers in dialysis patients: Secondary analysis of a randomized controlled trial

Published online: December 04, 2017Background/Aims: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. Methods: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. Results: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman’s rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. Conclusions: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.Matthew A. Roberts, Darsy Darssan, Sunil V. Badve, Robert P. Carroll, Magid A. Fahim, Brian A. Haluska, Carmel M. Hawley, Nicole M. Isbel, Mark R. Marshall, Elaine M. Pascoe, Eugenie Pedagogos, Helen L. Pilmore, Paul Snelling, Tony Stanton, Ken-Soon Tan, Andrew M. Tonkin, Liza A. Vergara, Francesco L. Ierin

Outcomes of corynebacterium peritonitis: a multicenter registry analysis

Background: Corynebacterium is a rare cause of peritonitis that is increasingly being recognized in peritoneal dialysis (PD) patients. The aims of this study were to compare Corynebacterium peritonitis outcomes with those of peritonitis caused by other organisms and to examine the effects of type and duration of antibiotic therapy on outcomes of Corynebacterium peritonitis. Methods: Using Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data, we included all PD patients who developed peritonitis in Australia between 2004 and 2014. The primary outcome was peritonitis cure by antibiotic therapy, defined as resolution of a peritonitis episode with antibiotics alone and without being complicated by recurrence, relapse, catheter removal, hemodialysis transfer, or death. Peritonitis outcomes were analyzed using multivariable logistic regression. Results: A total of 11,122 episodes of peritonitis in 5,367 patients were included. Of these, 162 episodes (1.5%) were due to Corynebacterium. Compared with Corynebacterium peritonitis, the odds of cure were lower in peritonitis due to Staphylococcus aureus (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45 – 0.97), Pseudomonas (OR 0.22, 95% CI 0.14 – 0.33), other gram-negative organisms (OR 0.52, 95% CI 0.35 – 0.75), fungi (OR 0.02, 95% CI 0.01 – 0.03), polymicrobial organisms (OR 0.32, 95% CI 0.22 – 0.47), and other organisms (OR 0.66, 95% CI 0.44 – 0.99) but similar for culture-negative and other gram-positive peritonitis. Similar results were observed for hemodialysis transfer and death. The outcomes of Corynebacterium peritonitis were not associated with the type of initial antibiotic selected (vancomycin vs cefazolin) or the duration of antibiotic therapy (≤ 14 days vs > 14 days). Conclusions: Outcomes for Corynebacterium peritonitis are generally favorable compared with other forms of peritonitis. Cure rates did not appear to differ if peritonitis was treated initially with vancomycin or cefazolin or if treatment duration was prolonged beyond 14 days.Htay Htay, Yeoungjee Cho, Elaine M. Pascoe, Darsy Darssan, Carmel Hawley, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville, Stephen P. McDonald and David W. Johnso

Multicenter registry analysis of center characteristics associated with technique failure in patients on incident peritoneal dialysis

Background and objectives: Technique failure is a major limitation of peritoneal dialysis. Our study aimed to identify center- and patient-level predictors of peritoneal dialysis technique failure. Design, setting, participants & measurements: All patients on incident peritoneal dialysis in Australia from 2004 to 2014 were included in the study using data from the Australia and New Zealand Dialysis and Transplant Registry. Center- and patient-level characteristics associated with technique failure were evaluated using Cox shared frailty models. Death-censored technique failure and cause-specific technique failure were analyzed as secondary outcomes. Results: The study included 9362 patients from 51 centers in Australia. The technique failure rate was 0.35 (95% confidence interval, 0.34 to 0.36) episodes per patient-year, with a sevenfold variation across centers that was mainly associated with center-level characteristics. Technique failure was significantly less likely in centers with larger proportions of patients treated with peritoneal dialysis (>29%; adjusted hazard ratio, 0.83; 95% confidence interval, 0.73 to 0.94) and more likely in smaller centers (<16 new patients per year; adjusted hazard ratio, 1.10; 95% confidence interval, 1.00 to 1.21) and centers with lower proportions of patients achieving target baseline serum phosphate levels (<40%; adjusted hazard ratio, 1.15; 95% confidence interval, 1.03 to 1.29). Similar results were observed for death-censored technique failure, except that center target phosphate achievement was not significantly associated. Technique failure due to infection, social reasons, mechanical causes, or death was variably associated with center size, proportion of patients on peritoneal dialysis, and/or target phosphate achievement, automated peritoneal dialysis exposure, icodextrin use, and antifungal use. The variation of hazards of technique failure across centers was reduced by 28% after adjusting for patient-specific factors and an additional 53% after adding center-specific factors. Conclusions: Technique failure varies widely across centers in Australia. A significant proportion of this variation is related to potentially modifiable center characteristics, including peritoneal dialysis center size, proportion of patients on peritoneal dialysis, and proportion of patients on peritoneal dialysis achieving target phosphate level.Htay Htay, Yeoungjee Cho, Elaine M. Pascoe, Darsy Darssan, Annie-Claire Nadeau-Fredett, Carmel Hawley, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville, Stephen P. McDonald, David W. Johnso

Meta-analysis for individual participant data with a continuous exposure: a case study

Objective Methods for meta-analysis of studies with individual participant data and continuous exposure variables are well described in the statistical literature but are not widely used in clinical and epidemiological research. The purpose of this case study is to make the methods more accessible. Study Design and Setting A two-stage process is demonstrated. Response curves are estimated separately for each study using fractional polynomials. The study-specific curves are then averaged pointwise over all studies at each value of the exposure. The averaging can be implemented using fixed effects or random effects methods. Results The methodology is illustrated using samples of real data with continuous outcome and exposure data and several covariates. The sample data set, segments of Stata and R code, and outputs are provided to enable replication of the results. Conclusion These methods and tools can be adapted to other situations, including for time-to-event or categorical outcomes, different ways of modelling exposure-outcome curves, and different strategies for covariate adjustment

The relationship between body mass index and organism-specific peritonitis

Background: Obesity is increasingly prevalent worldwide, and a greater number of patients initiate renal replacement therapy with a high body mass index (BMI). This study aimed to evaluate the association between BMI and organism-specific peritonitis. Methods: All adult patients who initiated peritoneal dialysis (PD) in Australia between January 2004 and December 2013 were included. Data were accessed through the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. The co-primary outcomes of this study were time to first organism-specific peritonitis episode, specifically gram-positive, gram-negative, culture-negative, and fungal. Secondary outcomes were individual rates of organism-specific peritonitis for the same 4 microbiological categories. Results: There were 7,381 peritonitis episodes among the 8,343 incident PD patients evaluated. After multivariable adjustment, obese patients (BMI 30 - 34.9 kg/m²) had an increased risk of fungal peritonitis (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.18 - 2.42), very obese patients (BMI ≥ 35 kg/m²) had a significantly higher risk of gram-positive peritonitis (HR 1.15, 95% CI 1.02 - 1.30), while both obese and very obese patients experienced significantly higher risks of gram-negative peritonitis (HR 1.29, 95% CI 1.11 - 1.50 and HR 1.30, 95% CI 1.08 - 1.57, respectively) compared with patients with normal BMI (20 - 24.9 kg/m²). Obesity and severe obesity were independently associated with increased incidence rate ratios of all forms of organism-specific peritonitis with a non-significant trend for severe obesity and gram-negative peritonitis association. Conclusion: Among Australian patients, obesity and severe obesity are associated with significantly increased rates of gram-positive, gram-negative, fungal, and culture-negative peritonitis.Dev Jegatheesan, David W. Johnson, Yeoungjee Cho, Elaine M. Pascoe, Darsy Darssan, Htay Htay, Carmel Hawley, Philip A. Clayton, Monique Borlace, Sunil V. Badve, Kamal Sud, Neil Boudville, Stephen P. McDonald and Annie-Claire Nadeau-Fredett

Design and methods of the REMOVAL-HD study: a tRial evaluating mid cut-off value membrane clearance of albumin and light chains in HaemoDialysis patients

Removal of uraemic toxins is inadequate using current dialysis strategies. A new class of dialysis membranes have been developed that allow clearance of larger middle molecules. The REMOVAL-HD study (a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HaemoDialysis patients) will address safety, efficacy and the impact on patient-centred outcomes with the use of a mid cut-off (MCO) dialyser in a chronic haemodialysis (HD) population.REMOVAL-HD is an open label, prospective, non-randomised, single-arm, multi-centre device study in 85 chronic HD participants. All visits will be conducted during regular HD sessions and participants will undergo a 1\ua0month wash-in period using a standardised high flux dialyser, 6\ua0months of intervention with a MCO dialyser and 1\ua0month of wash-out using a high flux dialyser. The primary endpoint is change in pre-dialysis concentrations of serum albumin, with secondary endpoints including the efficacy of clearance of free light chains and β-2 microglobulin, and patient-centred outcomes including quality of life, symptom burden, functional status, nutritional status, hospitalisation and death.MCO dialysers are a novel form of HD membrane. The REMOVAL-HD study is a pivotal study designed to monitor the immediate and medium-term effects following exposure to this dialyser.Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482 . Date of registration - 21/06/2016