Composite conditional likelihood for sparse clustered data

Sparse clustered data arise in finely stratified genetic and epidemiologic studies and pose at least two challenges to inference. First, it is difficult to model and interpret the full joint probability of dependent discrete data, which limits the utility of full likelihood methods. Second, standard methods for clustered data, such as pairwise likelihood and the generalized estimating function approach, are unsuitable when the data are sparse owing to the presence of many nuisance parameters. We present a composite conditional likelihood for use with sparse clustered data that provides valid inferences about covariate effects on both the marginal response probabilities and the intracluster pairwise association. Our primary focus is on sparse clustered binary data, in which case the method proposed utilizes doubly discordant quadruplets drawn from each stratum to conduct inference about the intracluster pairwise odds ratios. Copyright 2004 Royal Statistical Society.

Testing for qualitative interaction of multiple sources of informative dropout in longitudinal data

Longitudinal studies suffer from patient dropout. The dropout process may be informative if there exists an association between dropout patterns and the rate of change in the response over time. Multiple patterns are plausible in that different causes of dropout might contribute to different patterns. These multiple patterns can be dichotomized into two groups: quantitative and qualitative interaction. Quantitative interaction indicates that each of the multiple sources is biasing the estimate of the rate of change in the same direction, although with differing magnitudes. Alternatively, qualitative interaction results in the multiple sources biasing the estimate of the rate of change in opposing directions. Qualitative interaction is of special concern, since it is less likely to be detected by conventional methods and can lead to highly misleading slope estimates. We explore a test for qualitative interaction based on simultaneous confidence intervals. The test accommodates the realistic situation where reasons for dropout are not fully understood, or even entirely unknown. It allows for an additional level of clustering among participating subjects. We apply these methods to a study exploring tumor growth rates in mice as well as a longitudinal study exploring rates of change in cognitive functioning for Alzheimer's patients.

Robust inference for sparse cluster-correlated count data

Standard methods for the analysis of cluster-correlated count data fail to yield valid inferences when the study is finely stratified and the interest is in assessing the intracluster correlation structure. We present an approach, based upon exactly adjusting an estimating function for the bias induced by the fitting of stratum-specific effects, that requires modeling only the first two joint moments of the observations and that yields consistent and asymptotically normal estimators of the correlation parameters.Generalized estimating equation Household aggregation Intracluster correlation Nuisance parameters Poisson overdispersion Plug-in bias Profile estimating function Small geographic area

Low-chloride versus high-chloride hypertonic solution for the treatment of subarachnoid hemorrhage-related complications (The ACETatE trial): study protocol for a pilot randomized controlled trial

Abstract Background Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition that results from a ruptured cerebral vessel. Cerebral edema and vasospasm are common complications and frequently require treatment with hypertonic solutions, in particular hypertonic sodium chloride (NaCl). We have previously shown that hyperchloremia in patients with aSAH given hypertonic NaCl is associated with the development of acute kidney injury (AKI), which leads to higher morbidity and mortality. Our current trial aims to study the effect of two hypertonic solutions with different chloride content on serum chloride concentrations in patients with aSAH who are at risk for AKI. Methods A low ChloridE hyperTonic solution for brain Edema (ACETatE) is a single center, double-blinded, double-dummy pilot trial comparing bolus doses of 23.4% NaCl and 16.4% NaCl/Na-Acetate for the treatment of cerebral edema in patients with aSAH. All patients will be enrolled within 36 h following admission. Randomization will occur once patients who receive hypertonic treatment for cerebral edema develop hyperchloremia (serum Cl− concentration ≥ 109 mmol/L). Subsequent treatment will consist of either NaCl 23.4% or NaCl/Na-Acetate 16.4%. The primary outcome of this study will be the change in serum Cl− concentrations during treatment. Secondary outcomes will include incidence of AKI, mortality, changes in intracranial pressure, and extent of hypernatremia. Discussion In patients with aSAH, hyperchloremia is a known risk factor for subsequent development of AKI. The primary goal of this pilot study is to determine the effect of two hypertonic solutions with different Cl− content on serum Cl− concentrations in patients with aSAH who have already developed hyperchloremia. Data will be collected prospectively to determine the extent to which the choice of hypertonic saline solution affects subsequent serum Cl− concentrations and the occurrence of AKI. This approach will allow us to obtain preliminary data to design a large randomized trial assessing the effects of chloride-sparing hypertonic solutions on development of AKI in patients with SAH. This pilot study is the first to prospectively evaluate the relationship between hypertonic solution chloride content and its effect on serum electrolytes and renal function in aSAH patients at risk of AKI due to hyperchloremia. Trial registration Clinicaltrials.gov, NCT03204955. Registered on 28 June 2017

An Exploration of Subgroups of Mild Cognitive Impairment Based On Cognitive, Neuropsychiatric and Functional Features: Analysis of Data From the National Alzheimer's Coordinating Center

To empirically expand the existing subtypes of mild cognitive impairment (MCI) by incorporating information on neuropsychiatric and functional features, and to assess whether cerebrovascular disease (CVD) risk factors are associated with any of these subgroups. Latent class analysis using 1,655 patients with MCI. Participants in the Uniform Data Set (UDS) from 29 National Institutes of Health–supported Alzheimer's Disease Centers. Patients with a consensus diagnosis of MCI from each center and with a Mini-Mental State Examination score of 22 or greater. UDS cognitive battery, Neuropsychiatric Inventory Questionnaire, and Functional Assessment Questionnaire administered at initial visit. Seven empirically based subgroups of MCI were identified: 1) minimally impaired (relative frequency, 12%); 2) amnestic only (16%); 3) amnestic with functional and neuropsychiatric features (16%); 4) amnestic multidomain (12%); 5) amnestic multidomain with functional and neuropsychiatric features (12%); 6) functional and neuropsychiatric features (15%); and 7) executive function and language impairments (18%). Two of these subgroups with functional and neuropsychiatric features were at least 3.8 times more likely than the minimally impaired subgroup to have a Rosen-Hachinski score of 4 or greater, an indicator of probable CVD. Findings suggest that there are several distinct phenotypes of MCI characterized by prominent cognitive features, prominent functional features, and neuropsychiatric features or a combination of all three. Subgroups with functional and neuropsychiatric features are significantly more likely to have CVD, which suggests that there may be distinct differences in disease etiology from the other phenotypes

Correction to: Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial.

[This corrects the article DOI: 10.1186/s40560-020-00449-0.]

Low-chloride- versus high-chloride-containing hypertonic solution for the treatment of subarachnoid hemorrhage-related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial.

BACKGROUND: Recent reports have demonstrated that among patients with subarachnoid hemorrhage (SAH) treated with hypertonic NaCl, resultant hyperchloremia has been associated with the development of acute kidney injury (AKI). We report a trial comparing the effect of two hypertonic solutions with different chloride contents on the resultant serum chloride concentrations in SAH patients, with a primary outcome aimed at limiting chloride elevation. METHODS: A low ChloridE hyperTonic solution for brain Edema (ACETatE) trial is a single-center, double-blinded, double-dummy, randomized pilot trial comparing bolus infusions of 23.4% NaCl and 16.4% NaCl/Na-acetate for the treatment of cerebral edema in patients with SAH. Randomization occurred when patients developed hyperchloremia (serum Cl RESULTS: We enrolled 59 patients, of which 32 developed hyperchloremia and required hyperosmolar treatment. 15 patients were randomized to the 23.4% NaCl group, and 17 patients were randomized to the 16.4% NaCl/Na-acetate group. Although serum chloride levels increased similarly in both groups, the NaCl/Acetate group showed a significantly lower Cl CONCLUSIONS: Our pilot trial showed the feasibility and safety of replacing 23.4% NaCl infusions with 16.4% NaCl/Na-acetate infusions to treat cerebral edema in patients with SAH. The degree of hyperchloremia was similar in the two groups. 16.4% NaCl/Na-acetate infusions led to lower Cl TRIAL REGISTRATION: clinicaltrials.gov # NCT03204955, registered on 6/28/2017