Catherine A. Sugar

Finding the Number of Clusters in a Dataset: An Information-Theoretic Approach

One of the most difficult problems in cluster analysis is identifying the number of groups in a dataset. Most previously suggested approaches to this problem are either somewhat ad hoc or require parametric assumptions and complicated calculations. In this article we develop a simple, yet powerful nonparametric method for choosing the number of clusters based on distortion, a quantity that measures the average distance, per dimension, between each observation and its closest cluster center. Our technique is computationally efficient and straightforward to implement. We demonstrate empirically its effectiveness, not only for choosing the number of clusters, but also for identifying underlying structure, on a wide range of simulated and real world datasets. In addition, we give a rigorous theoretical justification for the method based on information-theoretic ideas. Specifically, results from the subfield of electrical engineering known as rate distortion theory allow us to describe the behavior of the distortion in both the presence and absence of clustering. Finally, we note that these ideas potentially can be extended to a wide range of other statistical model selection problems.

Clustering for Sparsely Sampled Functional Data

We develop a flexible model-based procedure for clustering functional data. The technique can be applied to all types of curve data but is particularly useful when individuals are observed at a sparse set of time points. In addition to producing final cluster assignments, the procedure generates predictions and confidence intervals for missing portions of curves. Our approach also provides many useful tools for evaluating the resulting models. Clustering can be assessed visually via low-dimensional representations of the curves, and the regions of greatest separation between clusters can be determined using a discriminant function. Finally, we extend the model to handle multiple functional and finite-dimensional covariates and show how it can be applied to standard finite-dimensional clustering problems involving missing data.

Social Cognition in Schizophrenia, Part 1: Performance Across Phase of Illness

Social cognitive impairments are consistently reported in schizophrenia and are associated with functional outcome. We currently know very little about whether these impairments are stable over the course of illness. In the current study, 3 different aspects of social cognition were assessed (emotion processing, Theory of Mind [ToM], and social relationship perception) at 3 distinct developmental phases of illness: prodromal, first episode, and chronic. In this cross-sectional study, participants included 50 individuals with the prodromal risk syndrome for psychosis and 34 demographically comparable controls, 81 first-episode schizophrenia patients and 46 demographically comparable controls, and 53 chronic schizophrenia patients and 47 demographically comparable controls. Outcome measures included total and subtest scores on 3 specialized measures of social cognition: (1) emotion processing assessed with the Mayer-Salovey-Caruso Emotional Intelligence Test, (2) ToM assessed with The Awareness of Social Inference Test, and (3) social relationship perception assessed the Relationships Across Domains Test. Social cognitive performance was impaired across all domains of social cognition and in all clinical samples. Group differences in performance were comparable across phase of illness, with no evidence of progression or improvement. Age had no significant effect on performance for either the clinical or the comparison groups. The findings suggest that social cognition in these 3 domains fits a stable pattern that has outcome and treatment implications. An accompanying article prospectively examines the longitudinal stability of social cognition and prediction of functional outcome in the first-episode sample.

Social Cognition in Schizophrenia, Part 2: 12-Month Stability and Prediction of Functional Outcome in First-Episode Patients

This study evaluated the longitudinal stability and functional correlates of social cognition during the early course of schizophrenia. Fifty-five first-episode schizophrenia patients completed baseline and 12-month follow-up assessments of 3 key domains of social cognition (emotional processing, theory of mind, and social/relationship perception), as well as clinical ratings of real-world functioning and symptoms. Scores on all 3 social cognitive tests demonstrated good longitudinal stability with test-retest correlations exceeding .70. Higher baseline and 12-month social cognition scores were both robustly associated with significantly better work functioning, independent living, and social functioning at the 12-month follow-up assessment. Furthermore, cross-lagged panel analyses were consistent with a causal model in which baseline social cognition drove later functional outcome in the domain of work, above and beyond the contribution of symptoms. Social cognitive impairments are relatively stable, functionally relevant features of early schizophrenia. These results extend findings from a companion study, which showed stable impairments across patients in prodromal, first-episode, and chronic phases of illness on the same measures. Social cognitive impairments may serve as useful vulnerability indicators and early clinical intervention targets.

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study

IntroductionCurcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimers disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD.MethodsWe performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimers Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimers Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Aβ1-40 and Aβ1-42 in plasma and levels of Aβ1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured.ResultsMean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL).ConclusionsCurcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound.Trial registrationClinicalTrials.gov Identifier: NCT00099710.

Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium

Previous structural neuroimaging studies of bipolar disorder have reported conflicting findings in limbic structures. Medication heterogeneity of patient samples may have contributed to these inconsistencies. Using structural magnetic resonance imaging we assessed whether lithium treatment was associated with differences in amygdala and hippocampal volumes in a sample of bipolar adults. A total of 49 magnetic resonance imaging scans were collected from patients who were currently treated with or without lithium. Amygdala and hippocampal volumes were analyzed using tensor-based morphometry. Statistical between-group comparisons of deformation maps showed that patients treated with lithium exhibited significantly increased volumes of the amygdala and hippocampus compared with patients who were not taking lithium. Our findings may help to explain previous inconsistencies in the bipolar literature.

The MCCB impairment profile for schizophrenia outpatients: Results from the MATRICS psychometric and standardization study

The MATRICS Psychometric and Standardization Study was conducted as a final stage in the development of the MATRICS Consensus Cognitive Battery (MCCB). The study included 176 persons with schizophrenia or schizoaffective disorder and 300 community residents. Data were analyzed to examine the cognitive profile of clinically stable schizophrenia patients on the MCCB. Secondarily, the data were analyzed to identify which combination of cognitive domains and corresponding cut-off scores best discriminated patients from community residents, and patients competitively employed vs. those not. Raw scores on the ten MCCB tests were entered into the MCCB scoring program which provided age- and gender-corrected T-scores on seven cognitive domains. To test for between-group differences, we conducted a 2 (group)×7 (cognitive domain) MANOVA with follow-up independent t-tests on the individual domains. Classification and regression trees (CART) were used for the discrimination analyses. Examination of patient T-scores across the seven cognitive domains revealed a relatively compact profile with T-scores ranging from 33.4 for speed of processing to 39.3 for reasoning and problem-solving. Speed of processing and social cognition best distinguished individuals with schizophrenia from community residents; speed of processing along with visual learning and attention/vigilance optimally distinguished patients competitively employed from those who were not. The cognitive profile findings provide a standard to which future studies can compare results from other schizophrenia samples and related disorders; the classification results point to specific areas and levels of cognitive impairment that may advance work rehabilitation efforts.

Mismatch Negativity, Social Cognition, and Functioning in Schizophrenia Patients

BACKGROUND Cognition and social cognition have been found to influence functional outcome in schizophrenia patients. However, little is known about the underlying neural substrates that are associated with social cognition or daily functioning. Prior studies found associations between mismatch negativity (MMN), an event-related potential response indexing early auditory processing, and functioning in schizophrenia patients. METHODS In this study, we examined MMN, social cognition (social perception and theory of mind), and four domains of functioning (work, independent living, social networks, and family networks) in 33 schizophrenia patients and 42 demographically comparable healthy control subjects. RESULTS Schizophrenia patients exhibited reduced MMN activity at frontocentral electrode sites compared with healthy control subjects. Within the schizophrenia sample, greater MMN activity at frontocentral sites correlated with better work and independent living (but not social or family networks) and with better social perception. CONCLUSIONS These results suggest that MMN activity is more closely tied to some outcome domains (work and independent living) than others. Mismatch negativity has been previously shown to be associated with basic cognition and functional outcome in schizophrenia, but these findings are the first, to our knowledge, to show MMN associations with social cognition. These results are consistent with cascade models of information processing in which deficits in early perceptual processing have a downstream impact on higher order social cognition and community functioning.

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia

Background Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. Methods Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. Results Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. Conclusions The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.

Frontal-Amygdala Connectivity Alterations During Emotion Downregulation in Bipolar I Disorder

BACKGROUND The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, downregulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion downregulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects. METHODS Thirty BPI and 26 control subjects underwent functional magnetic resonance imaging scanning while performing an emotion processing task with passive viewing and emotion downregulation conditions. Contrasts were made for each group comparing the downregulation and passive viewing conditions, and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological interaction analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC). RESULTS Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion downregulation tasks. Between-group analyses revealed similar activation of BPI and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus, and bilateral dorsal lateral prefrontal cortex during emotion downregulation in subjects with BPI. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared with subjects with BPI. CONCLUSIONS This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate, and subcortical structures, are present in BPI subjects, even while euthymic.