Biomedical subjects

Andrew C Leon

Publications and source records attributed to Andrew C Leon.

At least 19 recordsLinked to original sources

PubMed2007

A comparison of mixed-effects quantile stratification propensity adjustment strategies for longitudinal treatment effectiveness analyses of continuous outcomes.

The propensity adjustment is used to reduce bias in treatment effectiveness estimates from observational data. We show here that a mixed-effects implementation of the propensity adjustment can reduce bias in longitudinal studies of non-equivalent comparison groups. The strategy examined here involves two stages. Initially, a mixed-effects ordinal logistic regression model of propensity for treatment intensity includes variables that differentiate subjects who receive various doses of time-varying treatments. Second, a mixed-effects linear regression model compares the effectiveness of those ordinal doses on a continuous outcome over time. Here, a simulation study compares bias reduction that is achieved by implementing this propensity adjustment through various forms of stratification. The simulations demonstrate that bias decreased monotonically as the number of quantiles used for stratification increased from two to five. This was particularly pronounced with stronger effects of the confounding variables. The quartile and quintile strategies typically removed in excess of 80-90 per cent of the bias detected in unadjusted models; whereas a median-split approach removed from 20 to 45 per cent of bias. The approach is illustrated in an evaluation of the effectiveness of somatic treatments for major depression in a longitudinal, observational study of affective disorders.

Adult↗

PubMed2007

Bias reduction in effectiveness analyses of longitudinal ordinal doses with a mixed-effects propensity adjustment.

A mixed-effects propensity adjustment is described that can reduce bias in longitudinal studies involving non-equivalent comparison groups. There are two stages in this data analytic strategy. First, a model of propensity for treatment intensity examines variables that distinguish among subjects who receive various ordered doses of treatment across time using mixed-effects ordinal logistic regression. Second, the effectiveness model examines multiple times until recurrence to compare the ordered doses using a mixed-effects grouped-time survival model. Effectiveness analyses are initially stratified by propensity quintile. Then the quintile-specific results are pooled, assuming that there is not a propensity x treatment interaction. A Monte Carlo simulation study compares bias reduction in fully specified propensity model relative to misspecified models. In addition, type I error rate and statistical power are examined. The approach is illustrated by applying it to a longitudinal, observational study of maintenance treatment of major depression.

Adult↗

PubMed2006

Assessment of community functioning in people with schizophrenia and other severe mental illnesses: a white paper based on an NIMH-sponsored workshop.

People with schizophrenia frequently have significant problems in community functioning. Progress in developing effective interventions to ameliorate these problems has been slowed by the absence of reliable and valid measures that are suitable for use in clinical trials. The National Institute of Mental Health convened a workgroup in September 2005 to examine this issue and make recommendations to the field that would foster research in this area. This article reports on issues raised at the meeting. Many instruments have been developed to assess community functioning, but overall insufficient attention has been paid to psychometric issues and many instruments are not suitable for use in clinical trials. Consumer self-report, informant report, ratings by clinicians and trained raters, and behavioral assessment all can provide useful and valid information in some circumstances and may be practical for use in clinical trials. However, insufficient attention has been paid to when and how different forms of assessment and sources of information are useful or how to understand inconsistencies. A major limiting factor in development of reliable and valid instruments is failure to develop a suitable model of functioning and its primary mediators and moderators. Several examples that can guide thinking are presented. Finally, the field is limited by the absence of an objective gold standard of community functioning. Hence, outcomes must be evaluated in part by "clinical significance." This criterion is problematic because different observers and constituencies often have different opinions about what types of change are clinically important and how much change is significant.

Activities of Daily Living↗

PubMed2006

Prevention of missing data in clinical research studies.

Missing data is a problem that is ubiquitous to all clinical studies and a source of multiple problems from an analytic point of view (reduced statistical power, increased the type I error, bias) Statistical approaches have been developed to analyze data collected from trials with missing data. Understanding and implementing the appropriate statistical technique is essential but should be differentiated from preventive approaches that are designed to reduce rates of missing data In this article, we draw attention to these preventive efforts. Seven steps to minimizing the amount of missing data are defined as documentation, training, monitoring reports, patient contact, data entry and management, pilot studies, and communication. Although the implementation of these approaches is time consuming and costly, the overall quality of the study is increased. Despite efforts devoted to areas, no study is without missing data. Once the study is completed, it is essential to assess the pattern of missing data and apply the appropriate statistical analysis.

Bias↗

PubMed2006

Attrition in randomized controlled clinical trials: methodological issues in psychopharmacology.

Attrition is a ubiquitous problem in randomized controlled clinical trials (RCT) of psychotropic agents that can cause biased estimates of the treatment effect, reduce statistical power, and restrict the generalizability of results. The extent of the problem of attrition in central nervous system (CNS) trials is considered here and its consequences are examined. The taxonomy of missingness mechanisms is then briefly reviewed in order to introduce issues underlying the choice of data analytic strategies appropriate for RCTs with various forms of incomplete data. The convention of using last observation carried forward to accommodate attrition is discouraged because its assumptions are typically inappropriate for CNS RCTs, whereas multiple imputation strategies are more appropriate. Mixed-effects models often provide a useful data analytic strategy for attrition as do the pattern-mixture and propensity adjustments. Finally, investigators are encouraged to consider asking participants, at each assessment session, the likelihood of attendance at the subsequent assessment session. This information can be used to eliminate some of the very obstacles that lead to attrition, and can be incorporated in data analyses to reduce bias, but it will not eliminate all attrition bias.

Humans↗

PubMed2006

Psychopathology of panic attacks in panic disorder.

PURPOSE: This study examined the relationships among certain subtypes of panic attacks (full vs. limited symptom; spontaneous vs. situational) and between these subtypes, panic disorder subtypes, and other characteristics of panic disorder, especially agoraphobia. METHOD: Data were drawn from a large (n = 1,168) treatment study of panic disorder in which panic attacks were carefully subtyped and counted using a diary. Relationships between variables at baseline were examined primarily using non-parametric methods, and the course of improvement for panic subtypes among completers was plotted. RESULTS: The median number of spontaneous panic attacks per week at baseline was similar among patients with panic disorder without agoraphobia (PD), limited phobic avoidance (PDL), and agoraphobia (PDA). The median number of situational attacks and the median agoraphobia ratings rose progressively across diagnostic subtypes. Anticipatory anxiety, HAM-A, HAM-D, and disability scores were higher in PDA than in PD. Full and limited symptom panic attacks were positively correlated. The proportion of total attacks that were limited rose during the first two weeks of treatment, suggesting conversion of full to limited symptom attacks before complete disappearance. Spontaneous and situational attacks were correlated minimally or not at all. Agoraphobia ratings were more positively correlated with situational than with spontaneous panic attacks. Few of the correlations among measures at baseline were high. CONCLUSIONS: Full and limited symptom panic attacks differ primarily in severity. Spontaneous and situational attacks are relatively independent, and situational attacks are more closely related to agoraphobia. These findings are consistent with previous work suggesting that spontaneous attacks reflect a biological component, whereas situational attacks reflect a cognitive component in the psychopathology-- and possibly the pathogenesis-- of panic disorder. This provides a rationale for the use of combined pharmacotherapy and psychotherapy in the treatment of panic disorder. Future investigations of panic disorder should carefully separate panic attack subtypes.

Agoraphobia↗

PubMed2006

ACNP Task Force report on SSRIs and suicidal behavior in youth.

This Task Force report by the American College of Neuropsychopharmacology evaluates the safety and efficacy of selective serotonin reuptake inhibitor (SSRIs) antidepressants for depressed youth under 18 years. The report was undertaken after regulatory agencies in the United States and United Kingdom raised concerns in 2003 about the possibility that treatment of depression in children and adolescents with SSRIs may increase the risk of suicidal thinking or suicide attempts.

Adolescent↗

PubMed2006

Antidepressants and youth suicide in New York City, 1999-2002.

OBJECTIVE: To determine the proportion of youth suicides in New York City from 1999 to 2002 in which antidepressants were detected at autopsy. METHOD: This is a medical examiner surveillance study of suicides in New York City among those younger than 18 years of age. The outcome measure is serum toxicology for antidepressants. RESULTS: From 1999 through 2002, there were 41 individuals younger than 18 years of age among residents of New York City who committed suicide. Thirty-six (87.8%) had a serum toxicological analysis and an injury death interval of 3 days or less. There was one (2.8%) suicide in which both bupropion and sertraline were detected at the time of autopsy. Antidepressants were not detected in any of the other youth suicides. CONCLUSIONS: The detection of antidepressants at autopsy was quite rare in youth suicides in New York City from 1999 to 2002.

Adolescent↗

PubMed2006

The naturalistic course of unipolar major depression in the absence of somatic therapy.

The goal of the study was to describe the naturalistic course of unipolar major depression in subjects not receiving somatic therapy for their depressive illness. Affectively ill individuals were recruited into the Collaborative Depression Study and followed prospectively for up to 15 years. One hundred thirty subjects who recovered from their intake episode of major depression subsequently experienced a recurrence that went untreated for at least 4 weeks following onset of the recurrence. The duration of the recurrent episode was examined using survival analytic techniques. Of the 130 subjects, 46 obtained somatic therapy at some time during the course of their depressive illness, while 84 subjects received no somatic therapy throughout their entire depressive episode. Survival analysis, which accounts for these 46 individuals by censoring their episodes at the time treatment was obtained, yielded a median time to recovery of 23 weeks. In the subsample of 84 subjects whose depressive illness went untreated from its inception through its resolution, the median time to recovery was 13 weeks. These results suggest that there is a high rate of recovery in individuals not receiving somatic treatment of their depressive illness, particularly in the first 3 months of an episode. Because treatment-seeking behavior is known to be associated with a worse prognosis, 23 weeks probably represents a lower-limit approximation of the median duration of an untreated depressive episode.

Adolescent↗

PubMed2006

The face behind the mask: a developmental study.

Faces are a rich and available source of social information, and the representation for faces is robust in adults (i.e. the face detection effect; Purcell & Stewart, 1988). The current study compared the developmental trajectory of the robustness of face perception against the trajectory for a non-face object. Participants (5-35 years old) were presented with rapid (17 and 33 millisecond) presentations of face and house stimuli and were instructed to identify the object category of the stimulus (face or house). There was an interaction between object type and age such that the developmental slope for face identification was steeper than the slope for house identification for the 17-millisecond presentation. These data show that faces are processed in a different way than a non-face object during the period from middle childhood through adolescence and adulthood, and this differential processing may involve the massive amount of exposure we have to faces.

Adolescent↗

PubMed2006

Assessment of outcome in depression.

Valid and reliable methods of assessing outcome in depression are crucial to antidepressant efficacy studies but are also important for all studies that relate response to other variables. In this paper we review basic issues of reliability and validity associated with outcome measurement. We distinguish between scales or inventories designed for screening or diagnosis and those intended for outcome assessment. We note historical changes in patient selection (e.g. outpatients instead of inpatients, differentiating psychotic and non-psychotic) and how these changes affect commonly used scales such as the Hamilton Depression Rating Scale. We examine whether antidepressants with different mechanisms of action are best assessed with similar or different symptoms. And we review studies that have identified 'core' symptoms of depression and compare these findings to the magnitude of individual symptom change we found in five studies of selective serotonergic or nonadrenergic antidepressants.

Adrenergic Uptake Inhibitors↗

PubMed2006

Antidepressant treatment patterns in a novel methadone maintenance clinic targeting young adults an observational study.

This observational study examined the antidepressant treatment patterns of a novel New York City methadone maintenance treatment program (MMTP), founded for the treatment of adolescents and now targeting young adults and older patients with special problems. The goal of the study was to investigate demographic or clinical characteristics that were associated with prescribing patterns, as well as whether antidepressant use was associated with sobriety. The method of data collection was a thorough chart review. Antidepressant treatment was significantly associated with gender, education, marital status, and relapse. However, after controlling for demographic and clinical characteristics, antidepressant treatment was not significantly associated with a reduction in relapse risk. Further research is needed to explore these relationships, as well as their generalizability to adult methadone clinics, and to examine the underlying factors that lead to similarities and distinctions in antidepressant prescribing practices between various types of clinics (i.e., general outpatient vs. methadone maintenance).

Adolescent↗

PubMed2006

Distinguishing bipolar major depression from unipolar major depression with the screening assessment of depression-polarity (SAD-P).

BACKGROUND: Patients with bipolar I or II major depression are often misdiagnosed with unipolar major depression. The goal of this study was to develop and validate a brief instrument to screen for bipolar disorder in patients actively ill with major depression. METHOD: The sample consisted of subjects who enrolled in the National Institute of Mental Health-Collaborative Program on the Psychobiology of Depression-Clinical Studies from 1978 to 1981 during an episode of major depression and included 91 subjects with bipolar I major depression, 52 with bipolar II major depression, and 338 with unipolar major depression diagnosed according to Research Diagnostic Criteria. Most of the subjects were inpatients at the time of enrollment, and subjects were prospectively followed for up to 20 years. In order to create, test, and cross-validate the screening instrument, a split-sample data analytic procedure was performed. This procedure yielded 3 groups of subjects: the bipolar I index sample, the bipolar I cross-validation sample, and the bipolar II cross-validation sample. Each group included subjects with bipolar major depression and subjects with unipolar major depression. Within the bipolar I index sample, subjects with bipolar I major depression at study intake were compared with subjects with unipolar major depression at study intake on a pool of 59 sociodemographic and clinical candidate variables. The 3 variables showing the greatest disparity between bipolar I subjects and unipolar subjects were selected for the screen, the Screening Assessment of Depression-Polarity (SAD-P). The operating characteristics of the SAD-P were then examined within the bipolar I index sample, bipolar I cross-validation sample, and bipolar II cross-validation sample. RESULTS: The items selected for the screening instrument were (1) presence of delusions during the current episode of major depression, (2) number of prior episodes of major depression, and (3) family history of major depression or mania. The screen identified bipolar major depression with a sensitivity of 0.82 in the bipolar I index sample, 0.72 in the bipolar I cross-validation sample, and 0.58 in the bipolar II cross-validation sample. With regard to misclassifying subjects with unipolar major depression, the screen provided a positive predictive value of 0.36 in the bipolar I index sample, 0.29 in the bipolar I cross-validation sample, and 0.27 in the bipolar II cross-validation sample. CONCLUSION: We suggest using the 3-item SAD-P as a preliminary screen for bipolar disorder in patients who present with an active episode of major depression.

Adult↗

PubMed2005

Are there differences in the symptoms that respond to a selective serotonin or norepinephrine reuptake inhibitor?

BACKGROUND: We examined two previously published studies comparing a norepinephrine (NE) selective agent, reboxetine, and a serotonin (5-HT) selective agent, fluoxetine, to determine if these agents have different effects on individual depressive symptoms. METHODS: Both studies were 8-week, double-blind, comparison studies of men and women with DSM III-R major depression. Within-group effect sizes for individual symptom change on the Hamilton Depression Rating Scale (HAMD) were determined in the observed case samples and in patients for whom the symptom was relatively severe at baseline. We required that any significant differences in one sample be cross-validated in the second. RESULTS: Two hundred fifty-three subjects in study I and 168 subjects in study II were randomized to reboxetine or fluoxetine. In both samples, depressed mood, decreased interest, and psychic anxiety had the greatest change. Effect sizes for all HAMD symptoms were similar for the two drugs. No difference between groups in one sample was replicated in the second. Among subjects with severe symptoms, no significant differences were cross-validated. CONCLUSIONS: Reboxetine and fluoxetine appear to have similar effects on depressive symptoms. These data suggest that NE and 5-HT selective antidepressant drugs act through the same final common pathway and challenge the belief that symptom differences are useful for antidepressant selection.

Adrenergic Uptake Inhibitors↗

PubMed2005

Comparison of statistical methods for analysis of clustered binary observations.

When correlated observations are obtained in a randomized controlled trial, the assumption of independence among observations within cluster likely will not hold because the observations share the same cluster (e.g. clinic, physician, or subject). Further, the outcome measurements of interest are often binary. The objective of this paper is to compare the performance of four statistical methods for analysis of clustered binary observations: namely (1) full likelihood method; (2) penalized quasi-likelihood method; (3) generalized estimating equation method; (4) fixed-effects logistic regression method. The first three methods take correlations into account in inferential processes whereas the last method does not. Type I error rate, power, bias, and standard error are compared across the four statistical methods through computer simulations under varying effect sizes, intraclass correlation coefficients, number of clusters, and number of observations per cluster, including large numbers 20 and 100 of observations per cluster. The results show that the performance of the full likelihood and the penalized quasi-likelihood methods is superior for analysis of clustered binary observations, and is not necessarily inferior to that of the fixed-effects logistic regression fit even when within-cluster correlations are zero.

Cluster Analysis↗

PubMed2005

A mixed-effects quintile-stratified propensity adjustment for effectiveness analyses of ordered categorical doses.

Observational studies can be used to evaluate treatment effectiveness among patients with a broader range of illness severity than typically seen in randomized controlled clinical trials. However, there are several difficulties with observational evaluations including non-equivalent comparison groups, treatment doses and durations that vary widely, and, in longitudinal studies, multiple courses of treatment per subject. A mixed-effects approach to the propensity adjustment for non-equivalent comparison groups is described that can account for each of these perturbations. The strategy involves two stages. First, characteristics that distinguish among subjects who receive various levels of treatment are examined in a model of propensity for treatment intensity using mixed-effects ordinal logistic regression. Second, the propensity-stratified effectiveness of ordered categorical doses is compared in a mixed-effects grouped time survival model of time until recovery. The model is applied in a longitudinal, observational study of antidepressant effectiveness. Then a Monte Carlo simulation study indicates that the strategy has acceptable type I error rates and minimal bias in the estimates of treatment effectiveness. Statistical power exceeds 0.90 for an odds ratio of 1.5 with N = 250 and 500, and is acceptable for an odds ratio of 2.0 with N = 100. Nevertheless, with N = 100, the models that had high intraclass correlation coefficients had greater tendency towards non-convergence. This approach is a useful strategy for observational studies of treatment effectiveness. It is capable of adjusting for selection bias, incorporating multiple observations per subject, and comparing effectiveness of ordinal doses.

Antidepressive Agents↗

PubMed2005

A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia.

OBJECTIVE: On April 23, 2004, a joint meeting of the FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop guidelines for the design of clinical trials of cognitive-enhancing drugs for neurocognitive impairments in patients with schizophrenia. METHOD: Experts were asked to address specific questions relating to clinical trial design of adjunctive/co-treatment and broad spectrum agents. At the workshop, experts reviewed relevant evidence before offering the discussion panel proposed guidelines for a given subset of questions. The discussion panel, which consisted of presenters and representatives from FDA, NIMH, academia, and industry, deliberated to reach consensus on suggested guidelines. When evidence was insufficient, suggested guidelines represent the opinion of a cross-section of the presenters and discussion panel. RESULTS: Guidelines were developed for inclusion criteria, the use of co-primary outcome measures, and statistical approaches for study design. Consensus was achieved regarding diagnostic and concomitant medication inclusion criteria and on the use of cognitive screening measures. A key guideline was to limit the trial to patients in the residual phase of their illness, who have a predefined level of positive, negative, and affective symptoms. The most difficult issues were the feasibility of including a co-primary measure of functional improvement and the choice of comparator agent for a trial of a broad spectrum agent (with antipsychotic and cognitive-enhancing effects). CONCLUSIONS: The suggested guidelines represent reasonable starting points for trial design of cognitive-enhancing drugs, with the understanding that new data, subsequent findings, or other methodological considerations may lead to future modifications.

Antipsychotic Agents↗

PubMed2005

Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study.

CONTEXT: Evidence of psychosocial disability in bipolar disorder is based primarily on bipolar I disorder (BP-I) and does not relate disability to affective symptom severity and polarity or to bipolar II disorder (BP-II). OBJECTIVE: To provide detailed data on psychosocial disability in relation to symptom status during the long-term course of BP-I and BP-II. DESIGN: A naturalistic study with 20 years of prospective, systematic follow-up. SETTING: Inpatient and outpatient treatment facilities at 5 US academic centers. Patients One hundred fifty-eight patients with BP-I and 133 patients with BP-II who were followed up for a mean (SD) of 15 (4.8) years in the National Institute of Mental Health Collaborative Depression Study. MAIN OUTCOME MEASURES: The relationship, by random regression, between Range of Impaired Functioning Tool psychosocial impairment scores and affective symptom status in 1-month periods during the long-term course of illness from 6-month and yearly Longitudinal Interval Follow-up Evaluation interviews. RESULTS: Psychosocial impairment increases significantly with each increment in depressive symptom severity for BP-I and BP-II and with most increments in manic symptom severity for BP-I. Subsyndromal hypomanic symptoms are not disabling in BP-II, and they may even enhance functioning. Depressive symptoms are at least as disabling as manic or hypomanic symptoms at corresponding severity levels and, in some cases, significantly more so. At each level of depressive symptom severity, BP-I and BP-II are equally impairing. When asymptomatic, patients with bipolar disorder have good psychosocial functioning, although it is not as good as that of well controls. CONCLUSIONS: Psychosocial disability fluctuates in parallel with changes in affective symptom severity in BP-I and BP-II. Important findings for clinical management are the following: (1) depressive episodes and symptoms, which dominate the course of BP-I and BP-II, are equal to or more disabling than corresponding levels of manic or hypomanic symptoms; (2) subsyndromal depressive symptoms, but not subsyndromal manic or hypomanic symptoms, are associated with significant impairment; and (3) subsyndromal hypomanic symptoms appear to enhance functioning in BP-II.

Adaptation, Psychological↗