The Use of Putative Dialysis Initiation Time in Comparative Outcomes of Patients with Advanced Chronic Kidney Disease: Methodological Aspects

The latest data from the United States Renal Data Systems show over 134,000 individuals with end-stage kidney disease (ESKD) starting dialysis in the year 2019. ESKD patients on dialysis, the default treatment strategy, have high mortality and hospitalization, especially in the first year of dialysis. An alternative treatment strategy is (non-dialysis) conservative management (CM). The relative effectiveness of CM with respect to various patient outcomes, including survival, hospitalization, and health-related quality of life among others, especially in elderly ESKD or advanced chronic kidney disease patients with serious comorbidities, is an active area of research. A technical challenge inherent in comparing patient outcomes between CM and dialysis patient groups is that the start of follow-up time is “not defined” for patients on CM because they do not initiate dialysis. One solution is the use of putative dialysis initiation (PDI) time. In this work, we examine the validity of the use of PDI time to determine the start of follow-up for longitudinal retrospective and prospective cohort studies involving CM. We propose and assess the efficacy of estimating PDI time using linear mixed effects model of kidney function decline over time via simulation studies. We also illustrate how the estimated PDI time can be used to effectively estimate the survival distribution

Region-Referenced Spectral Power Dynamics of EEG Signals: A Hierarchical Modeling Approach

Functional brain imaging through electroencephalography (EEG) relies upon the analysis and interpretation of high-dimensional, spatially organized time series. We propose to represent time-localized frequency domain characterizations of EEG data as region-referenced functional data. This representation is coupled with a hierarchical modeling approach to multivariate functional observations. Within this familiar setting, we discuss how several prior models relate to structural assumptions about multivariate covariance operators. An overarching modeling framework, based on infinite factorial decompositions, is finally proposed to balance flexibility and efficiency in estimation. The motivating application stems from a study of implicit auditory learning, in which typically developing (TD) children, and children with autism spectrum disorder (ASD) were exposed to a continuous speech stream. Using the proposed model, we examine differential band power dynamics as brain function is interrogated throughout the duration of a computer-controlled experiment. Our work offers a novel look at previous findings in psychiatry, and provides further insights into the understanding of ASD. Our approach to inference is fully Bayesian and implemented in a highly optimized Rcpp package

Structural abnormalities in cortical volume, thickness, and surface area in 22q11.2 microdeletion syndrome: Relationship with psychotic symptoms.

Introduction22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins.MethodsHigh-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10-25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed.ResultsRelative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS.ConclusionDifferential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population

Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome.

22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk

High-Dimensional Fixed Effects Profiling Models and Applications in End-Stage Kidney Disease Patients: Current State and Future Directions

Profiling analysis aims to evaluate health care providers, including hospitals, nursing homes, or dialysis facilities among others with respect to a patient outcome, such as 30-day unplanned hospital readmission or mortality. Fixed effects (FE) profiling models have been developed over the last decade, motivated by the overall need to (a) improve accurate identification or “flagging” of under-performing providers, (b) relax assumptions inherent in random effects (RE) profiling models, and (c) take into consideration the unique disease characteristics and care/treatment processes of end-stage kidney disease (ESKD) patients on dialysis. In this paper, we review the current state of FE methodologies and their rationale in the ESKD population and illustrate applications in four key areas: profiling dialysis facilities for (1) patient hospitalizations over time (longitudinally) using standardized dynamic readmission ratio (SDRR), (2) identification of dialysis facility characteristics (e.g., staffing level) that contribute to hospital readmission, and (3) adverse recurrent events using standardized event ratio (SER). Also, we examine the operating characteristics with a focus on FE profiling models. Throughout these areas of applications to the ESKD population, we identify challenges for future research in both methodology and clinical studies

Association of US Dialysis Facility Staffing with Profiling of Hospital-Wide 30-Day Unplanned Readmission.

Background:Unplanned hospital readmissions are a major source of morbidity among dialysis patients, in whom the risk of hospital readmission is exceptionally high. The contribution of dialysis facility staffing to hospital readmission has been largely overlooked. Methods:Using annual data of dialysis patients from the United States Renal Data System from 2010 to 2013, we assessed dialysis facilities with a significantly worse (SW) and facilities with a nonsignificant (NS) standardized readmission ratio (SRR). SRR estimates were risk adjusted for patient factors, past year comorbidities, and index hospitalization characteristics. Facility staffing variables were compared between 2 exposure groups: facilities with SW and NS SRRs. Four measures of staffing, including patient-to-staffing ratio, were compared between SW and matched NS facilities. Results:About 136,000-148,000 dialysis patients with 269,000-319,000 index hospital discharges were used to identify facilities with SW and facilities with NS SRR annually. Approximately 3-4% of facilities were identified as having SW SRR among > 5,000 facilities annually. The percent of nurses-to-total staff was significantly lower in 2010 for SW facilities than in matched NS facilities (42.5 vs. 45.6%, p = 0.012), but this disparity was attenuated by 2013 (44.8 vs. 44.7%, p = 0.949). There was a higher patient-to-nurse ratio for SW facilities than for NS facilities (mean 16.4 vs. 15.2, p = 0.038) in 2010 as well, and the disparity was reduced by 2013. The trends were similar for patient-to-total staff and patient-to-registered nurse, but not statistically significant. Conclusions:This study found that dialysis facilities with SW 30-day readmission rates had lower proportions of nurses-to-total staff and higher patient-to-nurse ratios, but this disparity improved in recent years. Additional research is warranted focusing on how evidence-based staffing at dialysis facilities can contribute to reduction of hospital readmission, and this knowledge is needed to inform clinical practice guidelines and policy decisions regarding optimal dialysis patient staffing

A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome

Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6–17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant’s actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%–94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications