Serum creatinine as marker of kidney function in South Asians: a study of reduced GFR in adults in Pakistan

Migrant populations of South Asian origin have a higher risk for chronic kidney disease than the native whites. Several formulas have been developed to estimate kidney function from serum creatinine concentration. However, none of these has been validated in the South Asian population, which generally has different muscle mass composition than whites. A population-based cross-sectional study was performed on 262 individuals who were aged \u3e or = 40 yr in Karachi, Pakistan. Reduced GFR was defined as creatinine clearance (Ccr) measured in 24-h urine collection of /min per 1.73 m2. Creatinine excretion was compared with age- and gender-matched white individuals by comparison of observed versus expected results on the basis of a formula using t test. The agreement among Cockcroft Gault (CG) Ccr and Modification of Diet in Renal Disease (MDRD) Study GFR equations was assessed by regression analyses, and the degree of accuracy of estimated versus measured GFR was determined. Mean (95% confidence interval) creatinine excretion was 1.7 (1.0 to 2.4) mg/kg per d lower than expected for age- and gender-matched white individuals (P \u3c 0.001). The coefficient of determination for measured Ccr on the logarithmic scale was 66.7 and 55.6% for the CG and MDRD Study equations, respectively. The proportion of estimates within 20, 30, and 50% of measured Ccr values was 47.7 versus 32.8% (P \u3c 0.001), 64.9 versus 49.6% (P \u3c 0.001), and 79.4 versus 72.9 (P = 0.07) for CG versus MDRD Study equations, respectively. Lower mean creatinine excretion in these individuals may explain, in part, suboptimal agreement between estimated versus measured GFR. Inclusion of terms for ethnic and racial groups other than white and black might improve the performance of GFR estimating equations

Single-patient (n-of-1) trials: a pragmatic clinical decision methodology for patient-centered comparative effectiveness research

AbstractObjectiveTo raise awareness among clinicians and epidemiologists that single-patient (n-of-1) trials are potentially useful for informing personalized treatment decisions for patients with chronic conditions.Study Design and SettingWe reviewed the clinical and statistical literature on methods and applications of single-patient trials and then critically evaluated the needs for further methodological developments.ResultsExisting literature reports application of 2,154 single-patient trials in 108 studies for diverse clinical conditions; various recent commentaries advocate for wider application of such trials in clinical decision making. Preliminary evidence from several recent pilot acceptability studies suggests that single-patient trials have the potential for widespread acceptance by patients and clinicians as an effective modality for increasing the therapeutic precision. Bayesian and adaptive statistical methods hold promise for increasing the informational yield of single-patient trials while reducing participant burden, but are not widely used. Personalized applications of single-patient trials can be enhanced through further development and application of methodologies on adaptive trial design, stopping rules, network meta-analysis, washout methods, and methods for communicating trial findings to patients and clinicians.ConclusionsSingle-patient trials may be poised to emerge as an important part of the methodological armamentarium for comparative effectiveness research and patient-centered outcomes research. By permitting direct estimation of individual treatment effects, they can facilitate finely graded individualized care, enhance therapeutic precision, improve patient outcomes, and reduce costs

Hospital ownership and quality of care: what explains the different results?

Does quality of care systematically differ among government-owned, private not-for-profit, and for-profit hospitals? A large empirical literature provides conflicting evidance. Through quantitative review of 46 studies since 1990, we find that several study features that can explain divergent results: analytic methods, disease studied, and data sources. For unprofitable care, how studies handle market competition and regional differences account for substantial variation. Policymakers should be aware that differences in results appear to arise predominately from differences between studies' analytic methods. Moreover, conventional methods of meta-analysis synthesis should be applied with great caution given the considerable overlap among studied hospitals

Effects of study precision and risk of bias in networks of interventions: a network meta-epidemiological study

Background Empirical research has illustrated an association between study size and relative treatment effects, but conclusions have been inconsistent about the association of study size with the risk of bias items. Small studies give generally imprecisely estimated treatment effects, and study variance can serve as a surrogate for study size. Methods We conducted a network meta-epidemiological study analyzing 32 networks including 613 randomized controlled trials, and used Bayesian network meta-analysis and meta-regression models to evaluate the impact of trial characteristics and study variance on the results of network meta-analysis. We examined changes in relative effects and between-studies variation in network meta-regression models as a function of the variance of the observed effect size and indicators for the adequacy of each risk of bias item. Adjustment was performed both within and across networks, allowing for between-networks variability. Results Imprecise studies with large variances tended to exaggerate the effects of the active or new intervention in the majority of networks, with a ratio of odds ratios of 1.83 (95% CI: 1.09,3.32). Inappropriate or unclear conduct of random sequence generation and allocation concealment, as well as lack of blinding of patients and outcome assessors, did not materially impact on the summary results. Imprecise studies also appeared to be more prone to inadequate conduct. Conclusions Compared to more precise studies, studies with large variance may give substantially different answers that alter the results of network meta-analyses for dichotomous outcome

Closing the Gap between Methodologists and End-Users: R as a Computational Back-End

The R environment provides a natural platform for developing new statistical methods due to the mathematical expressiveness of the language, the large number of existing libraries, and the active developer community. One drawback to R, however, is the learning curve; programming is a deterrent to non-technical users, who typically prefer graphical user interfaces (GUIs) to command line environments. Thus, while statisticians develop new methods in R, practitioners are often behind in terms of the statistical techniques they use as they rely on GUI applications. Meta-analysis is an instructive example; cutting-edge meta-analysis methods are often ignored by the overwhelming majority of practitioners, in part because they have no easy way of applying them. This paper proposes a strategy to close the gap between the statistical state-of-the-science and what is applied in practice. We present open-source meta-analysis software that uses R as the underlying statistical engine, and Python for the GUI. We present a framework that allows methodologists to implement new methods in R that are then automatically integrated into the GUI for use by end-users, so long as the programmer conforms to our interface. Such an approach allows an intuitive interface for non-technical users while leveraging the latest advanced statistical methods implemented by methodologists

Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients

Background Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin‐inhibitors (CNI) are combined with corticosteroids and a proliferation‐inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. Objectives This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. Search methods We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co‐ordinator using search terms relevant to this review. Selection criteria All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. Data collection and analysis Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random‐effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). Main results We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported. MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death‐censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all‐cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy‐proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody‐treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta‐regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro‐emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures. Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue‐invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. Authors' conclusions MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue‐invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on

Melatonin in Youth: N-of-1 trials in a stimulant-treated ADHD Population (MYNAP): study protocol for a randomized controlled trial

Attention-deficit/hyperactivity disorder (ADHD) is a common neurological disorder affecting 5\ua0% of children worldwide. A prevalent problem for children with ADHD is initial insomnia. The gold standard treatment to manage ADHD symptoms is stimulant medications, which may exacerbate the severity of existing initial insomnia. Currently, no gold standard treatment option exists for initial insomnia for these children. Melatonin, a hormone and a popular natural health product, is commonly provided to children by parents and recommended by healthcare providers, but high quality pediatric evidence is lacking.This trial is a multicenter randomized triple-blind, placebo-controlled, parallel-group, randomized, controlled trial (RCT), in which each participant is offered an N-of-1 trial. An N-of-1 trial is a multiple-crossover, randomized, controlled trial conducted in a single individual. For the N-of-1 trial, each participant will undergo three pairs of treatment/placebo periods; each period is 1\ua0week in length. Half the participants will have melatonin in the first period, the other half will start with placebo, and this will make up the parallel-group RCT. The primary outcome will be mean difference in sleep onset latency as measured by sleep diaries. A comparison of treatment effects yielded by the RCT data versus the aggregated N-of-1 trial data will also be assessed.This trial will provide rigorous evidence for the effectiveness of melatonin in children with ADHD on stimulants who experience initial insomnia. Further, this study will provide the first prospectively planned head-to-head comparison of RCT data with pooled data from a series of N-of-1 trials. Aggregated N-of-1 trials may be a powerful tool to produce high quality clinical trial evidence.ClinicalTrials.gov, NCT02333149 . Registered on 16 December 2014. Australian New Zealand Clinical Trials Registry, ACTRN12614000542695 . Registered on 21 May 2014

External validation of the DHAKA score and comparison with the current IMCI algorithm for the assessment of dehydration in children with diarrhoea: a prospective cohort study

BACKGROUND: Dehydration due to diarrhoea is a leading cause of child death worldwide, yet no clinical tools for assessing dehydration have been validated in resource-limited settings. The Dehydration: Assessing Kids Accurately (DHAKA) score was derived for assessing dehydration in children with diarrhoea in a low-income country setting. In this study, we aimed to externally validate the DHAKA score in a new population of children and compare its accuracy and reliability to the current Integrated Management of Childhood Illness (IMCI) algorithm. METHODS: DHAKA was a prospective cohort study done in children younger than 60 months presenting to the International Centre for Diarrhoeal Disease Research, Bangladesh, with acute diarrhoea (defined by WHO as three or more loose stools per day for less than 14 days). Local nurses assessed children and classified their dehydration status using both the DHAKA score and the IMCI algorithm. Serial weights were obtained and dehydration status was established by percentage weight change with rehydration. We did regression analyses to validate the DHAKA score and compared the accuracy and reliability of the DHAKA score and IMCI algorithm with receiver operator characteristic (ROC) curves and the weighted kappa statistic. This study was registered with ClinicalTrials.gov, number NCT02007733. FINDINGS: Between March 22, 2015, and May 15, 2015, 496 patients were included in our primary analyses. On the basis of our criterion standard, 242 (49%) of 496 children had no dehydration, 184 (37%) of 496 had some dehydration, and 70 (14%) of 496 had severe dehydration. In multivariable regression analyses, each 1-point increase in the DHAKA score predicted an increase of 0.6% in the percentage dehydration of the child and increased the odds of both some and severe dehydration by a factor of 1.4. Both the accuracy and reliability of the DHAKA score were significantly greater than those of the IMCI algorithm. INTERPRETATION: The DHAKA score is the first clinical tool for assessing dehydration in children with acute diarrhoea to be externally validated in a low-income country. Further validation studies in a diverse range of settings and paediatric populations are warranted. FUNDING: National Institutes of Health Fogarty International Center