Helena C. Kraemer

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.

Coming to Terms With Risk Factors for Eating Disorders: Application of Risk Terminology and Suggestions for a General Taxonomy.

The aims of the present review are to apply a recent risk factor approach (H. C. Kraemer et al., 1997) to putative risk factors for eating disorders, to order these along a timeline, and to deduce general taxonomic questions. Putative risk factors were classified according to risk factor type, outcome (anorexia nervosa, bulimia nervosa, binge-eating disorder, full vs. partial syndromes), and additional factor characteristics (specificity, potency, need for replication). Few of the putative risk factors were reported to precede the onset of the disorder. Many factors were general risk factors; only few differentiated between the 3 eating disorder syndromes. Common risk factors from longitudinal and cross-sectional studies were gender, ethnicity, early childhood eating and gastrointestinal problems, elevated weight and shape concerns, negative self-evaluation, sexual abuse and other adverse experiences, and general psychiatric morbidity. Suggestions are made for the conceptualization of future risk factor studies.

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.

A Genomic Screen of Autism: Evidence for a Multilocus Etiology

We have conducted a genome screen of autism, by linkage analysis in an initial set of 90 multiplex sibships, with parents, containing 97 independent affected sib pairs (ASPs), with follow-up in 49 additional multiplex sibships, containing 50 ASPs. In total, 519 markers were genotyped, including 362 for the initial screen, and an additional 157 were genotyped in the follow-up. As a control, we also included in the analysis unaffected sibs, which provided 51 discordant sib pairs (DSPs) for the initial screen and 29 for the follow-up. In the initial phase of the work, we observed increased identity by descent (IBD) in the ASPs (sharing of 51.6%) compared with the DSPs (sharing of 50.8%). The excess sharing in the ASPs could not be attributed to the effect of a small number of loci but, rather, was due to the modest increase in the entire distribution of IBD. These results are most compatible with a model specifying a large number of loci (perhaps >/=15) and are less compatible with models specifying </=10 loci. The largest LOD score obtained in the initial scan was for a marker on chromosome 1p; this region also showed positive sharing in the replication family set, giving a maximum multipoint LOD score of 2.15 for both sets combined. Thus, there may exist a gene of moderate effect in this region. We had only modestly positive or negative linkage evidence in candidate regions identified in other studies. Our results suggest that positional cloning of susceptibility loci by linkage analysis may be a formidable task and that other approaches may be necessary.

Evaluating medical tests : objective and quantitative guidelines

Introduction Disorder and Diagnosis Definition Test Protocol, Response, Referent Families of Test Referents Population and Sampling Sensitivity and Specificity The Signal Detection Approach Predictive Values The Bayesian Approach, Risk Ratios and Odds Ratio Efficiency Choosing Clinically Optimal Tests Taking Test Costs into Account Costworthy Tests Basic Issues in Using Multiple Tests Evaluating Batteries of Medical Tests Optimal Sequences Evaluating Batteries of Medical Tests Optimal Scores Evaluating Batteries of Prognostic Tests with Variable Follow-Up Times Evaluation of Medical Tests The Past, Present and Future

Size of treatment effects and their importance to clinical research and practice.

In randomized clinical trails (RCTs), effect sizes seen in earlier studies guide both the choice of the effect size that sets the appropriate threshold of clinical significance and the rationale to believe that the true effect size is above that threshold worth pursuing in an RCT. That threshold is used to determine the necessary sample size for the proposed RCT. Once the RCT is done, the data generated are used to estimate the true effect size and its confidence interval. Clinical significance is assessed by comparing the true effect size to the threshold effect size. In subsequent meta-analysis, this effect size is combined with others, ultimately to determine whether treatment (T) is clinically significantly better than control (C). Thus, effect sizes play an important role both in designing RCTs and in interpreting their results; but specifically which effect size? We review the principles of statistical significance, power, and meta-analysis, and commonly used effect sizes. The commonly used effect sizes are limited in conveying clinical significance. We recommend three equivalent effect sizes: number needed to treat, area under the receiver operating characteristic curve comparing T and C responses, and success rate difference, chosen specifically to convey clinical significance.

The role and interpretation of pilot studies in clinical research.

Pilot studies represent a fundamental phase of the research process. The purpose of conducting a pilot study is to examine the feasibility of an approach that is intended to be used in a larger scale study. The roles and limitations of pilot studies are described here using a clinical trial as an example. A pilot study can be used to evaluate the feasibility of recruitment, randomization, retention, assessment procedures, new methods, and implementation of the novel intervention. A pilot study is not a hypothesis testing study. Safety, efficacy and effectiveness are not evaluated in a pilot. Contrary to tradition, a pilot study does not provide a meaningful effect size estimate for planning subsequent studies due to the imprecision inherent in data from small samples. Feasibility results do not necessarily generalize beyond the inclusion and exclusion criteria of the pilot design. A pilot study is a requisite initial step in exploring a novel intervention or an innovative application of an intervention. Pilot results can inform feasibility and identify modifications needed in the design of a larger, ensuing hypothesis testing study. Investigators should be forthright in stating these objectives of a pilot study. Grant reviewers and other stakeholders should expect no more.

Pursuit of thinness and onset of eating disorder symptoms in a community sample of adolescent girls: A three-year prospective analysis.

Community-based prospective studies are needed to shed light on mechanisms that may influence development of eating disorders and identify variables that could serve as potential targets for prevention efforts. In this paper we examine level of weight preoccupation and other variables prospectively associated with age of onset of eating disorder symptoms over a 3-year interval in a community sample (N = 939) of young adolescent girls. 3.6% (32/887) experienced onset of symptoms over the interval. Only one factor, a measure of Weight Concerns, was significantly associated with onset (p < .001). Girls scoring in the highest quartile on the measure of Weight Concerns had the shortest survival time (12% incidence by age 14.5) and those scoring in the lowest quartile had the highest survival time (2% incidence by age 14.5; p < .001). This finding is consistent with both theoretical and clinical perspectives and represents one of the first prospective demonstrations of a linkage between weight and body shape concerns and later onset of eating disorder symptoms. An understanding of the independent variables that predispose girls to development of symptoms is a useful step towards the establishment of a rational basis for the choice of a prevention intervention target.

Facial emotion discrimination: II. Behavioral findings in depression

The facial discrimination tasks described in part I (Erwin et al., 1992) were administered to a sample of 14 patients with depression and 14 normal controls matched for sex (12 women, 2 men) and balanced for age and sociodemographic characteristics. Patients performed more poorly on measures of sensitivity for happy discrimination and specificity for sad discrimination, and had a higher negative bias across tasks. Severity of negative affect was correlated with poorer performance for patients. The results suggest that depression is associated with an impaired ability to recognize facial displays of emotion.

Report by the ACNP Task Force on Response and Remission in Major Depressive Disorder

This report summarizes recommendations from the ACNP Task Force on the conceptualization of remission and its implications for defining recovery, relapse, recurrence, and response for clinical investigators and practicing clinicians. Given the strong implications of remission for better function and a better prognosis, remission is a valid, clinically relevant end point for both practitioners and investigators. Not all depressed patients, however, will reach remission. Response is a less desirable primary outcome in trials because it depends highly on the initial (often single) baseline measure of symptom severity. It is recommended that remission be ascribed after 3 consecutive weeks during which minimal symptom status (absence of both sadness and reduced interest/pleasure along with the presence of fewer than three of the remaining seven DSM-IV-TR diagnostic criterion symptoms) is maintained. Once achieved, remission can only be lost if followed by a relapse. Recovery is ascribed after at least 4 months following the onset of remission, during which a relapse has not occurred. Recovery, once achieved, can only be lost if followed by a recurrence. Day-to-day functioning and quality of life are important secondary end points, but they were not included in the proposed definitions of response, remission, recovery, relapse, or recurrence. These recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission. These recommendations were based largely on logic, the need for internal consistency, and clinical experience owing to the lack of empirical evidence to test these concepts. Research to evaluate these recommendations empirically is needed.