AN INTRODUCTION TO GENERALIZED LINEAR MIXED MODELS

The generalized linear mixed model (GLMM) generalizes the standard linear model in three ways: accommodation of non-normally distributed responses, specification of a possibly non-linear link between the mean of the response and the predictors, and allowance for some forms of correlation in the data. As such, GLMMs have broad utility and are of great practical importance. Two special cases of the GLMM are the linear mixed model (LMM) and the generalized linear model (GLM). Despite the utility of such models, their use has been limited due to the lack of reliable, well-tested estimation and testing methods. I first describe and give examples of GLMMs and then discuss methods of estimation including maximum likelihood, generalized estimating equations, and penalized quasi-likelihood. Finally I briefly survey current research efforts in GLMMs

Use of Antihypertensive Agents and Association With Risk of Adverse Outcomes in Chronic Kidney Disease: Focus on Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

Background Our objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD . Methods and Results We studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time-dependent angiotensin-converting enzyme inhibitor or angiotensin receptor blocker , β-blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2-3 CKD ] versus advanced disease [stage 4-5 CKD ]). During median follow-up of 7.5 years, renin-angiotensin-aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β-blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD . Renin-angiotensin-aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67-0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67-0.90), regardless of severity of CKD . Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD . β-Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29-2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43), especially during early CKD ( P<0.05 for interaction). Conclusions Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD . Use of agents besides angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD

Nonparametric Machine Learning and Efficient Computation with Bayesian Additive Regression Trees: The BART R Package

In this article, we introduce the BART R package which is an acronym for Bayesian additive regression trees. BART is a Bayesian nonparametric, machine learning, ensemble predictive modeling method for continuous, binary, categorical and time-to-event outcomes. Furthermore, BART is a tree-based, black-box method which fits the outcome to an arbitrary random function, f , of the covariates. The BART technique is relatively computationally efficient as compared to its competitors, but large sample sizes can be demanding. Therefore, the BART package includes efficient state-of-the-art implementations for continuous, binary, categorical and time-to-event outcomes that can take advantage of modern off-the-shelf hardware and software multi-threading technology. The BART package is written in C++ for both programmer and execution efficiency. The BART package takes advantage of multi-threading via forking as provided by the parallel package and OpenMP when available and supported by the platform. The ensemble of binary trees produced by a BART fit can be stored and re-used later via the R predict function. In addition to being an R package, the installed BART routines can be called directly from C++. The BART package provides the tools for your BART toolbox

Tubular secretion of creatinine and kidney function: an observational study.

BackgroundPrior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.MethodsTo fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.ResultsObserved CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.ConclusionsThese data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR

Frailty and the Burden of Concurrent and Incident Disability in Patients With Cirrhosis: A Prospective Cohort Study.

Frailty results from the chronic effects of malnutrition and muscle wasting in patients with cirrhosis. It is well-established that frailty is strongly associated with mortality in this population. However, little is known of its relationship with physical disability, a critical patient-centered outcome. Adults with cirrhosis underwent outpatient testing of frailty using the Liver Frailty Index (LFI) and disability using activities of daily living (ADL; range 0-6) and Instrumental ADL (IADL; range 0-8) scales at one center between 2012 and 2016. We used adjusted multilevel logistic mixed-effects regression to test the association between frailty and current disability (impairment with ≥1 ADL or IADL) and incident disability at 6 months among those without baseline disability. Of the 983 participants, 20% were robust, 32% were less robust, 33% were prefrail, and 15% were frail; 587 (60%) had at least 1 assessment. The percentage of participants with at least 1 baseline ADL or IADL impairment was 28% and 37%, respectively. In adjusted regression models, each point LFI increase was associated with a 3.3 and 4.6 higher odds of current difficulty with at least 1 ADL and IADL (P < 0.001 for each), respectively. Among participants without baseline disability, each point LFI increase was associated with a 2.6 and 1.7 higher odds of having difficulty with at least 1 ADL and IADL at 6 months, respectively. Conclusion: Frailty is strongly associated with concurrent and incident disability in patients with cirrhosis. In the clinic, the LFI can be used to identify those in greatest need for additional support/resources to maintain functional independence. In research settings, the LFI may help to identify an enriched population for clinical trials of interventions aimed at those most vulnerable to disability

Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes.

ObjectiveTo compare different blood pressure (BP) levels in their association with the risk of renal outcomes in type 1 diabetes and to determine whether an intensive glycemic control strategy modifies this association.Research design and methodsWe included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) (sustained estimated glomerular filtration rate <60 mL/min/1.73 m2).ResultsDuring a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the <120 mmHg range was associated with a 0.59 times higher risk of macroalbuminuria (95% CI 0.37-0.95) and a 0.32 times higher risk of stage III CKD (95% CI 0.14-0.75) compared with SBPs between 130 and 140 mmHg. DBP in the <70 mmHg range were associated with a 0.73 times higher risk of macroalbuminuria (95% CI 0.44-1.18) and a 0.47 times higher risk of stage III CKD (95% CI 0.21-1.05) compared with DBPs between 80 and 90 mmHg. No interaction was noted between BP and prior DCCT-assigned glycemic control strategy (all P > 0.05).ConclusionsA lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes