Ellen Stover

The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity.

OBJECTIVE The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National Institute of Mental Healths Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. METHOD The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. RESULTS The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. CONCLUSIONS The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. It may also aid evaluation of cognitive remediation strategies.

Approaching a consensus cognitive battery for clinical trials in schizophrenia: The NIMH-MATRICS conference to select cognitive domains and test criteria

To stimulate the development of new drugs for the cognitive deficits of schizophrenia, the National Institute of Mental Health (NIMH) established the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative. This article presents an overview of decisions from the first MATRICS consensus conference. The goals of the meeting were to 1) identify the cognitive domains that should be represented in a consensus cognitive battery and 2) prioritize key criteria for selection of tests for the battery. Seven cognitive domains were selected based on a review of the literature and input from experts: working memory, attention/vigilance, verbal learning and memory, visual learning and memory, reasoning and problem solving, speed of processing, and social cognition. Based on discussions at this meeting, five criteria were considered essential for test selection: good test-retest reliability, high utility as a repeated measure, relationship to functional outcome, potential response to pharmacologic agents, and practicality/tolerability. The results from this meeting constitute the initial steps for reaching a consensus cognitive battery for clinical trials in schizophrenia.

The MATRICS Consensus Cognitive Battery, Part 2: Co-Norming and Standardization

OBJECTIVE The consensus cognitive battery developed by the National Institute of Mental Healths (NIMHs) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. METHOD The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. RESULTS Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. CONCLUSIONS Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores.

Functional Co-Primary Measures for Clinical Trials in Schizophrenia: Results From the MATRICS Psychometric and Standardization Study

OBJECTIVE During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i.e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. METHOD As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). RESULTS Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. CONCLUSIONS Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures.

Effects of a behavioral intervention to reduce risk of transmission among people living with HIV: The Healthy Living Project randomized controlled study

Context:The US Centers for Disease Control and Prevention (CDC) strongly recommend comprehensive risk counceling and services for people living with HIV (PLH); yet, there are no evidence-based counseling protocols. Objective:To examine the effect of a 15-session, individually delivered, cognitive behavioral intervention on a diverse sample of PLH at risk of transmitting to others. Design:This was a multisite, 2-group, randomized, controlled trial. Participants:Nine hundred thirty-six HIV-infected participants considered to be at risk of transmitting HIV of 3818 persons screened were randomized into the trial. Participants were recruited in Los Angeles, Milwaukee, New York, and San Francisco. Intervention:Fifteen 90-minute individually delivered intervention sessions were divided into 3 modules: stress, coping, and adjustment; safer behaviors; and health behaviors. The control group received no intervention until the trial was completed. Both groups completed follow-up assessments at 5, 10, 15, 20, and 25 months after randomization. Main Outcome Measure:Transmission risk, as measured by the number of unprotected sexual risk acts with persons of HIV-negative or unknown status, was the main outcome measure. Results:Overall, a significance difference in mean transmission risk acts was shown between the intervention and control arms over 5 to 25 months (χ2 = 16.0, degrees of freedom = 5; P = 0.007). The greatest reduction occurred at the 20-month follow-up, with a 36% reduction in the intervention group compared with the control group. Conclusion:Cognitive behavioral intervention programs can effectively reduce the potential of HIV transmission to others among PLH who report significant transmission risk behavior.

Evaluation of Functionally Meaningful Measures for Clinical Trials of Cognition Enhancement in Schizophrenia

OBJECTIVE Because reduction of psychotic symptoms in schizophrenia does not result in adequate community functioning, efforts have shifted to other areas, such as cognitive impairment. The U.S. Food and Drug Administration requires that drugs for cognition enhancement in schizophrenia show improvement on two distinct outcome measures in clinical trials: an accepted cognitive performance battery and a functionally meaningful coprimary measure. The authors examined the reliability, validity, and practicality of functionally meaningful measures. METHOD In this four-site validation study, schizophrenia patients were assessed at baseline (N=166) and 4 weeks later (N=144) on performance-based (Independent Living Scales, Test of Adaptive Behavior in Schizophrenia [TABS], and UCSD Performance-based Skills Assessment [UPSA]) and interview-based (Cognitive Assessment Interview and Clinical Global Impression Scale for Cognition) candidate coprimary measures. In addition, cognitive performance, community functioning, and clinical symptoms were assessed. Both full and short forms of the performance-based measures were evaluated. RESULTS All measures were well tolerated by patients, had adequate test-retest reliability, and showed good utility as a repeated measure. Measures differed in their correlation with cognitive performance, with performance-based measures having stronger correlations than interview-based measures. None of the measures had notable floor or ceiling effects or missing data. CONCLUSIONS Among the full-form measures, the UPSA was judged to have the strongest overall properties. Among the short forms, the TABS and UPSA appeared to have the strongest features. Use of the short forms saves time, but at the cost of lower test-retest reliability and weaker correlations with cognitive performance.

Neurobehavioral outcomes in diseases of childhood: Individual change models for pediatric human immunodeficiency viruses.

The growing incidence of human immunodeficiency virus-1 (HIV-1) and acquired immunodeficiency syndrome (AIDS) in children is a major public health problem. Current research emphasizes treatments for ameliorating deleterious effects on the childs neurological and behavioral development. This article outlines approaches to the assessment of individual change that may provide alternatives to more traditional approaches to the assessment of neurobehavioral outcomes in children with chronic diseases. These approaches provide more precise conceptualizations of changes that lead directly to statistical designs and measurement strategies for assessing effects of HIV-1 and AIDS on development. Such assessments can be superimposed on current clinical trial methodologies to evaluate the efficacy of pharmacological and behavioral interventions designed to improve quality of life in HIV-1 infected children.

NIMH Initiatives to Facilitate Collaborations Among Industry, Academia, and Government for the Discovery and Clinical Testing of Novel Models and Drugs for Psychiatric Disorders

There is an urgent need to transform basic research discoveries into tools for treatment and prevention of mental illnesses. This article presents an overview of the National Institute of Mental Health (NIMH) programs and resources to address the challenges and opportunities in psychiatric drug development starting at the point of discovery through the early phases of translational research. We summarize NIMH and selected National Institutes of Health (NIH) efforts to stimulate translation of basic and clinical neuroscience findings into novel targets, models, compounds, and strategies for the development of innovative therapeutics for psychiatric disorders. Examples of collaborations and partnerships among NIMH/NIH, academia, and industry are highlighted.

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Payoff from AIDS behavioral prevention research

Publisher Summary Despite the remarkable improvement in HIV treatment, there is still no cure or preventive vaccine. For every person in sub-Saharan Africa that starts on HIV Highly Active Antiretroviral Therapy (HAART), conservatively four persons become HIV infected. HIV infection is preventable, primarily through behavior change. In the 25 years during which HIV/STD prevention research has been conducted in the US, much has been learned about the theoretical variables that need to be considered when predicting and changing high-risk HIV-related behaviors. The model of the reproductive rate of sexually transmitted diseases includes: infectivity or transmissibility, interaction rates between susceptibles and infectors, and duration of infectiousness. HIV/STD prevention research tests ways to change behaviors that place persons at risk for HIV/STD infection, while HIV/STD operational research identifies methods to translate effective programs to public health settings as rapidly as possible. Prevention and operations research are conducted at multiple levels: individual, couple, family, institutional, community, and societal. Targeted outcomes are self-report of safer sexual behavior (correct and consistent condom use, fewer partners, monogamy by partners, moderate alcohol use, and adoption of safer drug-using practices) and lower incidence of STDs and HIV. The involvement of the community in the development and review of the conduct of HIV/STD research has been a hallmark of this work. Prevention research efforts have been designed for vulnerable groups who are at higher risk for both HIV and co-occurring medical conditions that are mediated by health behaviors.